bluuebunny/crossref_metadata_2025_split huggingface dataset:
YOUNG PLASMA REJUVENATES BLOOD DNA METHYLATION PROFILE, PROLONGS MEAN LIFESPAN AND IMPROVES HEALTH IN OLD RATS
Authors: Chiavellini Priscila , Canatelli Mallat Martina , Lehmann Marianne , Zoller Joseph A. , Gordevicius Juozas , Gallardo Maria D. , Pasquini Diana C. , Lacunza Ezequiel , Herenu Claudia B. , Morel Gustavo R. , Horvath Steve , Goya Rodolfo G. 
Published: December 2022

ABSTRACTThere is converging evidence that young blood conveys cells, vesicles and molecules able to revitalize function and restore organ integrity in old individuals. Here, we assessed the effects of young rat plasma on the lifespan, epigenetic age and healthspan of old female rats. Beginning at 25.3 months of age, a group of 9 rats (group T) was intraperitoneally injected with plasma from young rats (2 months) until their natural death. A group of control rats of the same age, received no treatment. Blood samples were collected every other week. Survival curves showed that from age 26 to 30 months, none of the T animals died, whereas the survival curve of C rats began to decline at age 26 months. The external appearance of the T rats was healthier than that of the C counterparts. Blood DNA methylation (DNAm) was assessed using the HorvathMammalMethylChip320. Blood DNAm age versus chronological age showed that DNAm age in young animals increased faster than chronological age then slowed down progressively, entering a plateau after 27 months. Immediately after the start of the treatment, the DNAm age (i.e., epigenetic age) of the treated rats fell below the DNAm age of controls and remained consistently lower until the end of their lives. Assessment of each experimental group showed that the blood DNA methylation levels of 1638 CpGs were different between treated and control blood samples (false discovery rate q-value<0.05). Of these, 1007 CpGs exhibited increased methylation, with age while 631 CpGs showed decreased methylation levels. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific GO term enrichment related to the insulin-like factors (IGFs) pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement, readily translatable to the clinic.
The landscape of alternative polyadenylation during EMT and its regulation by the RNA-binding protein Quaking
Authors: Neumann Daniel P. , Pillman Katherine A. , Dredge B. Kate , Bert Andrew G. , Bracken Cameron P. , Hollier Brett G. , Selth Luke A. , Beilharz Traude H. , Goodall Gregory J. , Gregory Philip A. 
Published: December 2022

AbstractEpithelial-mesenchymal transition (EMT) plays important roles in tumour progression and is orchestrated by dynamic changes in gene expression. While it is well established that post-transcriptional regulation plays a significant role in EMT, the extent of alternative polyadenylation (APA) during EMT has not yet been explored. Using 3’ end anchored RNA sequencing, we mapped the alternative polyadenylation landscape (APA) following TGF-β-mediated induction of EMT in human mammary epithelial cells and found APA generally causes 3’UTR lengthening during this cell state transition. Analysis of the RNA-binding protein Quaking (QKI), a splicing factor induced during EMT, revealed enrichment of its binding adjacent to cleavage and polyadenylation sites within 3’UTRs. Following QKI knockdown, APA of many transcripts are altered to produce predominantly shorter 3’UTRs associated with reduced gene expression. Among these, QKI binds to its own cleavage site to produce a transcript with a longer 3’UTR. These findings reveal extensive changes in APA occur during EMT and identify a novel function for QKI in this process.
Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner
Authors: Fu Xiuling , Zhuang Qiang , Babarinde Isaac A. , Shi Liyang , Ma Gang , Hu Haoqing , Li Yuhao , Chen Jiao , Xiao Zhen , Deng Boping , Sun Li , Jauch Ralf , Hutchins Andrew P. 
Published: December 2022

AbstractSomatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are highly resistant to reprogramming. There must be barriers that block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using a variety of oncogenic transgenes, and discovered transformed cell lines that remain compatible with reprogramming when transfected withOct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed very early, whilst other lines seemed to progress through a normal-looking reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperactive epigenetic state in some of the transformed cells. This study reveals that the barriers underlying resistance to reprogramming vary between the different transformation methods.Key findingsSomatic cell reprogramming of transformed cells is context-specificInhibition of MEK converts some cell lines to reprogramming-capableTransformed cell lines are characterized by a hyperactive chromatin stateMEK inhibition indirectly affects chromatin to enable reprogramming
An ESCRT-dependent pathway coordinates Nuclear and Cytoplasmic Spatial Protein Quality Control at Nuclear Vacuolar Junctions
Authors: Sontag Emily M. , Morales-Polanco Fabián , Chen Jian-Hua , McDermott Gerry , Dolan Patrick T. , Gestaut Dan , Le Gros Mark A. , Larabell Carolyn , Frydman Judith 
Published: December 2022

AbstractEffective Protein Quality Control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we elucidate the coordination of nuclear and cytoplasmic spatial PQC. While cytoplasmic misfolded proteins concentrate in a cytoplasmic, perinuclear Juxta Nuclear Quality control compartment (JUNQ), nuclear misfolded proteins sequester into a perinucleolar IntraNuclear Quality control compartment (INQ). Particle tracking reveals the INQ and JUNQ converge to face each other across the nuclear envelope at a site proximal to the Nuclear-Vacuolar Junction (NVJ) marked by perinuclear ESCRT-II/-III protein Chm7. Strikingly, this ESCRT-dependent convergence facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. We propose perinuclear ESCRT coordinates spatial PQC at nuclear-vacuolar contacts to facilitate vacuolar clearance of nuclear and cytoplasmic misfolded proteins.
Effect of mitochondrial circulation on mitochondrial age density distribution
Authors: Kuznetsov Ivan A. , Kuznetsov Andrey V. 
Published: December 2022

AbstractRecent publications report that although the mitochondria population in an axon can be quickly replaced by a combination of retrograde and anterograde axonal transport (often within less than 24 hours), the axon contains much older mitochondria. This suggests that not all mitochondria that reach the soma are degraded and that some are recirculating back into the axon. To explain this, we developed a model that simulates mitochondria distribution when a portion of mitochondria that return to the soma are redirected back to the axon rather than being destroyed in somatic lysosomes. Utilizing the developed model, we studied how the percentage of returning mitochondria affects the mean age and age density distributions of mitochondria at different distances from the soma. We also investigated whether turning off the mitochondrial anchoring switch can reduce the mean age of mitochondria. For this purpose, we studied the effect of reducing the value of a parameter that characterizes the probability of mitochondria transition to the stationary (anchored) state. The reduction in mitochondria mean age observed when the anchoring probability is reduced suggests that some injured neurons may be saved if the percentage of stationary mitochondria is decreased. The replacement of possibly damaged stationary mitochondria with newly synthesized ones may restore the energy supply in an injured axon. We also performed a sensitivity study of the mean age of stationary mitochondria to the parameter that determines what portion of mitochondria re-enter the axon and the parameter that determines the probability of mitochondria transition to the stationary state.
Dietary sugar and protein exert opposing effects on key larval growth and metabolic regulators, theDrosophilainsulin-like peptides Dilp2 and Dilp6
Authors: Suzawa Miyuki , McPherson W. Kyle , Van Gorder Elizabeth E. , Reddy Shivani , Hilovsky Dalton L. , Keliinui Cami N. , Jamali Leila A. , Bland Michelle L. 
Published: December 2022

ABSTRACTNutrient intake drives secretion of insulin and insulin-like peptides that stimulate glucose uptake, nutrient storage, protein synthesis and cell growth. TheDrosophilagenome encodes seven insulin-like peptides (Dilps) that bind to a single known insulin receptor to drive growth and nutrient storage. Whether Dilps respond uniformly to changes in dietary nutrients is unknown. Here we characterized the endocrine response to starvation and dietary sugar and protein in mid-third instarDrosophilalarvae, measuring circulating Dilp2, derived from insulin-producing cells in the brain, and Dilp6, produced by the fat body. Starvation led to a 90% reduction in circulating Dilp2 without affecting circulating Dilp6 levels. Dietary protein, but not sugar, restored hemolymph Dilp2 from starved levels, while elevated and imbalanced ratios of sugar to protein led to modest reductions in circulating Dilp2. In contrast, hemolymph Dilp6 was increased by a sugar-only diet. Surprisingly, dietary protein strongly reduced circulating Dilp6 levels. Dietary sugar drives glycogen and triglyceride storage, and levels of these stored nutrients positively correlate with Dilp6. Protein in the diet promotes whole-animal growth, which correlates strongly with circulating Dilp2. Our data show that Dilp2 and Dilp6 secretion are regulated in opposite ways by distinct dietary nutrients. These findings raise the question of how the single known insulin receptor integrates divergent signals from distinct Dilps to control growth and metabolism.
Characterization of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Conformational States on Infectious Virus Particles
Authors: Nguyen Hanh T. , Wang Qian , Anang Saumya , Sodroski Joseph G. 
Published: December 2022

ABSTRACTHuman immunodeficiency virus (HIV-1) entry into cells involves triggering of the viral envelope glycoprotein (Env) trimer ((gp120/gp41)3) by the primary receptor, CD4, and coreceptors, CCR5 or CXCR4. The pretriggered (State-1) conformation of the mature (cleaved) Env is targeted by broadly neutralizing antibodies (bNAbs), which are inefficiently elicited compared with poorly neutralizing antibodies (pNAbs). Here we characterize variants of the moderately triggerable HIV-1AD8Env on virions produced by an infectious molecular proviral clone; such virions contain more cleaved Env than pseudotyped viruses. We identified three types of cleaved wild-type AD8 Env trimers on virions: 1) State-1-like trimers preferentially recognized by bNAbs and exhibiting strong subunit association; 2) trimers recognized by pNAbs directed against the gp120 coreceptor-binding region and exhibiting weak, detergent-sensitive subunit association; and 3) a minor gp41-only population. The first Env population was enriched and the other Env populations reduced by introducing State-1-stabilizing changes in the AD8 Env or by treatment of the virions with crosslinker or the State-1-preferring entry inhibitor, BMS-806. These stabilized AD8 Envs were also more resistant to gp120 shedding induced by a CD4-mimetic compound or by incubation on ice. Conversely, a State-1-destabilized, CD4-independent AD8 Env variant exhibited weaker bNAb recognition and stronger pNAb recognition. Similar relationships between Env triggerability and antigenicity/shedding propensity on virions were observed for other HIV-1 strains. Our results show that State-1 Envs on virions can be significantly enriched by optimizing Env cleavage; stabilizing the pretriggered conformation by Env modification, crosslinking or BMS-806 treatment; strengthening Env subunit interactions; and using CD4-negative producer cells.IMPORTANCEEfforts to develop an effective HIV-1 vaccine have been frustrated by the inability to elicit broad neutralizing antibodies that recognize multiple virus strains. Such antibodies are able to bind a particular shape of the HIV-1 envelope glycoprotein trimer, as it exists on a viral membrane but before engaging receptors on the host cell. Here, we establish simple yet powerful assays to characterize the envelope glycoproteins in a natural context on virus particles. We find that, depending on the HIV-1 strain, some envelope glycoproteins change shape and fall apart, creating decoys that can potentially divert the host immune response. We identify requirements to keep the relevant envelope glycoprotein target for broad neutralizing antibodies intact on virus-like particles. These studies suggest strategies that should facilitate efforts to produce and use virus-like particles as vaccine immunogens.
Candida khanbhaisp. nov., a new clinically relevant yeast within theCandida haemuloniispecies complex
Authors: de Jong Auke W. , Al-Obaid Khaled , Tap Ratna Mohd , van den Ende Bert Gerrits , Groenewald Marizeth , Joseph Leena , Ahmad Suhail , Hagen Ferry 
Published: December 2022

AbstractInvasive fungal infections caused by non-albicans Candidaspecies are increasingly reported. Recent advances in diagnostic and molecular tools enabled better identification and detection of these emerging pathogenic yeasts. Several of these emerging species belong to theCandida haemuloniispecies complex, which attracted much attention due to the rapid global emergence of its multi-drug resistant memberCandida auris. Here, we describe a new clinically relevant yeast isolated from geographically distinct regions, representing the proposed novel speciesCandida khanbhai, member of theC. haemuloniispecies complex. Moreover, several members of theC. haemuloniispecies complex were observed to be invalidly described, includingCandida aurisandCandida vulturna. Hence, the opportunity was taken to correct this here, formally validating the names of various yeast species.
N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections
Authors: Feng Jian , Meng Wen , Chen Luping , Zhang Xinquan , Markazi Ashley , Yuan Weiming , Huang Yufei , Gao Shou-Jiang 
Published: December 2022

AbstractMitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also itsN6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1β, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1β, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections.IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found thatN6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.
Evaluating the use of social contact data to produce age-specific forecasts of SARS-CoV-2 incidence
Authors: Munday James D , Abbott Sam , Meakin Sophie , Funk Sebastian 
Published: December 2022

AbstractShort-term forecasts can provide predictions of how an epidemic will change in the near future and form a central part of outbreak mitigation and control. Renewal-equation based models are increasingly popular. They infer key epidemiological parameters from historical epidemiological data and forecast future epidemic dynamics without requiring complex mechanistic assumptions. However, these models typically ignore interaction between age-groups, partly due to challenges in parameterising a time varying interaction matrix. Social contact data collected regularly by the CoMix survey during the COVID-19 epidemic in England, provide a means to inform interaction between age-groups in real-time.We developed an age-specific forecasting framework and applied it to two age-stratified time-series: incidence of SARS-CoV-2 infection, estimated from a national infection and antibody prevalence survey; and, reported cases according to the UK national COVID-19 dashboard. Jointly fitting our model to social contact data from the CoMix study, we inferred a time-varying next generation matrix which we used to project infections and cases in the four weeks following each of 29 forecast dates between October 2021 and November 2022. We evaluated the forecasts using proper scoring rules and compared performance with three other models with alternative data and specifications alongside two naive baseline models.Overall, incorporating age-interaction improved forecasts of infections and the CoMix-data-informed model was the best performing model at time horizons between two and four weeks. However, this was not true when forecasting cases. We found that age-group-interaction was most important for predicting cases in children and older adults. The contact-data-informed models performed best during the winter months of 2020 - 2021, but performed comparatively poorly in other periods. We highlight challenges regarding the incorporation of contact data in forecasting and offer proposals as to how to extend and adapt our approach, which may lead to more successful forecasts in future.
Back to the future: omnipresence of fetal influence on the human brain through the lifespan
Authors: Walhovd Kristine B. , Krogsrud Stine Kleppe , Amlien Inge K. , Sørensen Øystein , Wang Yunpeng , Bråthen Anne Cecilie Sjøli , Overbye Knut , Kransberg Jonas , Mowinckel Athanasia M. , Magnussen Fredrik , Herud Martine , Håberg Asta K. , Fjell Anders M. , Vidal-Piñeiro Didac 
Published: December 2022

AbstractHuman fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and life-long positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4-82 years of age, w/ 386 monozygotic twins, followed for up to 8.3 years w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.
Investigating graph neural network for RNA structural embedding
Authors: Opuu Vaitea , Bret Hélène 
Published: December 2022

AbstractThe biological function of natural non-coding RNAs (ncRNA) is tightly bound to their molecular structure. Sequence analyses such as multiple sequence alignments (MSA) are the bread and butter of bio-molecules functional analysis; however, analyzing sequence and structure simultaneously is a difficult task. In this work, we propose CARNAGE (Clustering/Alignment of RNA with Graph-network Embedding), which leverages a graph neural network encoder to imprint structural information into a sequence-like embedding; therefore, downstream sequence analyses now account implicitly for structural constraints. In contrast to the traditional “supervised” alignment approaches, we trained our network on a masking problem, independent from the alignment or clustering problem. Our method is very versatile and has shown good performances in 1) designing RNAs sequences, 2) clustering sequences, and 3) aligning multiple sequences only using the simplest Needleman and Wunsch’s algorithm. Not only can this approach be readily extended to RNA tridimensional structures, but it can also be applied to proteins.
Effect of acute ultraviolet radiation onGalleria mellonellahealth and immunity
Authors: Sabockyte Ausrine , McAllister Samuel , Coates Christopher J. , Lim Jenson 
Published: December 2022

ABSTRACTFor humans, acute and chronic overexposure to ultraviolet (UV) radiation can cause tissue damage in the form of sunburn and promote cancer(s). The immune-modulating properties of UV radiation and health-related consequences are not well known. Herein, we used the larvae of the wax moth (Galleria mellonella) to determine UV-driven changes in cellular components of innate immunity. From immune cell (haemocyte) reactivity and the production of antimicrobial factors, these insects share many functional similarities with mammalian innate immunity. After exposing insects to UVA or UVB, we monitored larval viability, susceptibility to infection, haemolymph (blood) physiology and faecal discharge. Prolonged exposure of larvae to UVB coincided with decreased survival, enhanced susceptibility to bacterial challenge, melanin synthesis in the haemolymph, compromised haemocyte functionality and changes in faecal (bacterial) content. We contendG. mellonellais a reliablein vivomodel for assessing the impact of UV exposure at the whole organism and cellular levels.