bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finding the strongest gene drive: Simulations reveal unexpected performance differences betweenAnopheleshoming suppression drive candidates
Authors: Champer Samuel E. , Kim Isabel K. , Clark Andrew G. , Messer Philipp W. , Champer Jackson 
Published: March 2022

AbstractRecent experiments have produced severalAnopheles gambiaehoming gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on thezpgpromoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we re-analyze the data of each of these gene drives and suggest an alternative interpretation of their performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on thenospromoter may prove to be more promising candidates for future development due to potentially superior performance.
Cortical integration of higher-order thalamic inputs is lineage-dependent
Authors: Buchan Matthew J. , Mahfooz Kashif , van Rheede Joram J. , Gothard Gemma , Avery Sophie V. , Ellender Tommas J. , Newey Sarah E. , Akerman Colin J. 
Published: March 2022

AbstractPrimary sensory cortex receives and integrates inputs from first-order and higher-order thalamic nuclei. First-order inputs convey sensory information from the periphery and exhibit simple response properties, whereas higher-order inputs exhibit more complex response properties, provide contextual feedback, and can modulate first-order inputs. Here we show that the way in which cortical neurons integrate these thalamic inputs, reflects the progenitor cell from which the cortical neurons derive. Within layer 4 of mouse primary somatosensory cortex, excitatory neurons that derive from apical intermediate progenitors exhibit multi-whisker response properties and receive higher-order thalamic input, in a manner consistent with their dendritic morphology. These properties depend upon the expression levels of the transcription factor Lhx2, which when increased, abolishes the higher-order properties of apical intermediate progenitor-derived neurons, and disrupts the induction of sensory-evoked plasticity. These data reveal a lineage-dependent mechanism that establishes the integration and functional contribution of higher-order thalamic inputs within cortex.
Wild common crossbills produce redder body feathers when their wings are clipped
Authors: Fernández-Eslava Blanca , Cantarero Alejandro , Alonso Daniel , Alonso-Alvarez Carlos 
Published: March 2022

AbstractThe animal signaling theory posits that conspicuous colorations exhibited by many animals have evolved as reliable signals of individual quality. Red carotenoid-based ornaments may depend on enzymatic transformations (oxidation) of dietary yellow carotenoids, which could occur in the inner mitochondrial membrane (IMM). Thus, carotenoid ketolation and cell respiration could share the same biochemical pathways. Accordingly, the level of trait expression (redness) would directly reveal the efficiency of individuals’ metabolism and hence, the bearer quality in an unfalsifiable way. Different avian studies have described that the flying effort may induce oxidative stress. A redox metabolism modified during the flight could thus influence the carotenoid conversion rate and, ultimately, animal coloration. Here, we aimed to infer the link between red carotenoid-based ornament expression and flight metabolism by increasing flying effort in wild male common crossbillsLoxia curvirostra(Linnaeus). In this order, 295 adult males were captured during winter in an Iberian population. Half of the birds were experimentally handicapped through wing feather clipping to increase their flying effort, the other half being used as a control group. The rump feathers were also plucked in all the birds to stimulate plumage regrown of a small surface during a short time-lapse. Thirty-four birds with fully grown rump feathers could be recaptured in the subsequent weeks. Among them, male crossbills with experimentally impaired flying capacity showed redder rump feathers than controls. This result would support the hypothesis that the flying metabolism influences the redox enzymatic reactions required for converting yellow dietary carotenoids to red ketocarotenoids.Summary statementCarotenoid-based colorations may depend on pigment enzymatic transformations linked to mitochondrial function. The flight metabolism could influence this. Here, common crossbills with clipped wings produced redder feathers than controls.
miR-34a negatively regulates cell cycle factor Cdt2/DTL in HPV infected Cervical Cancer Cells
Authors: Singh Garima , Sharma Sonika Kumari , Singh Samarendra Kumar 
Published: March 2022

AbstractMicroRNAs have emerged as an important factor in regulating cell cycle and various other cellular processes. Aberration in microRNAs has been linked with development of several cancers and other diseases but still very little is known about the mechanism behind their function in regulating cellular processes. 99% of cervical cancer is caused by the infection of high-risk HPVs (HR HPVs) which suppresses multiple tumor suppressors and checkpoint factors of the host cell. It also stabilizes oncogenic proteins, one of them is Cdt2/DTL which promotes cell transformation and proliferation. In this study, we have reported that in cervical cancer cell lines miR-34a by targeting HPV E6 protein, regulates Cdt2/DTL protein level and leads to its destabilization. Destabilization of Cdt2 stabilizes onco-suppressor proteins like p21 and Set8 in these cell lines. We have also shown that the overexpression of miR-34a suppresses cell proliferation, invasion and migration capabilities of HPV positive cervical cancer cells which was reverted by overexpression of either HPV E6 or Cdt2 genes. This is the first-ever report to show that miR-34a regulates cell cycle factor Cdt2 by suppressing viral E6 protein level, which opens up the scope of exploring miR-34a as a specific therapy for cervical cancer treatment.Abstract Figure
Effects of haemosporidian co-infection and parasitemia on reproductive strategies in a polymorphic species
Authors: Delefortrie Zoé , Gante Hugo F. , Gordo Oscar , Schwab Kristopher R. , Gonser Rusty A. 
Published: March 2022

ABSTRACTHost-parasite interactions play a significant role in evolution. Parasite infections impose fitness costs that can trigger trade-off responses in host reproductive strategies. Individuals can invest limited resources in parasite defense, such as stimulating the immune system, or perform terminal reproductive investment. Here, we investigated how haemosporidian co-infection and parasitemia influence different reproductive strategies in a polymorphic bird species (the white-throated sparrow, Zonotrichia albicollis). We provided an account of the impacts of co-infection and parasitemia on host reproductive success and reproductive strategies in response to parasite infection. We tested the effect of co-infection and parasitemia on reproductive success (fledgling number, extra-pair paternity, ratio social/genetic offspring) and the effect of parental infection on nestling quality (mean nestling growth rate and body condition). We found that co-infection increases reproductive extra-pair paternity and nestling mean body condition. Parental high parasitemia positively impacts the ratio of genetic offspring belonging to the social father and has mixed results on nestling quality. We observed that co-infection in females and parasitemia in males might trigger a switch in reproductive strategy towards a terminal investment for co-infected individuals. In contrast, high parasitemia in females negatively impacted their offspring fitness, possibly due to the reallocation of resources for fighting the infection.
Dynamic adaptation of sequential action benefits from cortico-basal ganglia-related temporal variability
Authors: Ferguson Lachlan A. , Matamales Miriam , Balleine Bernard W. , Bertran-Gonzalez Jesus 
Published: March 2022

AbstractPerforming several actions in swift succession is often necessary to exploit known contingencies in the environment. However, in order to remain successful when contingency rules change, streamlined action sequences must be adaptable. Here, by combining analyses of behavioural microstructure with circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relies on post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). Using a two-lever instrumental task, we found that mice build successful action sequences by first establishing action scaffolds, from which they dynamically elongate as task requirements extend. Specific interruption of the M1→DLS circuit altered these dynamics, prompting actions that were less variable in their timing, overall reducing opportunities for success. Our results reveal a role for M1→DLS circuitry in setting the exploration/exploitation balance that is required for adaptively guiding the timing and success of instrumental action. Based on evidence from transsynaptic tracing experiments, we propose that such function may involve additional downstream subcortical processing relating to collateralisation of descending motor pathways to multiple basal ganglia centres.
Uracil/H+ symport by the FurE transporter challenges the rocking-bundle mechanism of transport in APC transporters
Authors: Zantza Iliana , Papadaki Georgia F. , Raniolo Stefano , Pyrris Yiannis , Lambrinidis George , Limongelli Vittorio , Diallinas George , Mikros Emmanuel 
Published: March 2022

AbstractTransporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H+ symporter of Aspergillus nidulans has been used as a model protein to address structure-function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called ‘rocking-bundle’ mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H+ by FurE, using path collective variable, funnel metadynamics and rationally designed mutational analysis. Our study reveals a step-wise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that the FurE symporter, and probably structurally similar transporters, functions as a multi-step gated pore, rather than employing ‘rocking’ of compact domains, as generally proposed for APC transporters. In addition, our work further supports the emerging concept that specific elements of cytosolic terminal regions of transporters might be functionally important.
Stability and learning in excitatory synapses by nonlinear inhibitory plasticity
Authors: Miehl Christoph , Gjorgjieva Julijana 
Published: March 2022

AbstractSynaptic changes underlie learning and memory formation in the brain. But synaptic plasticity of excitatory synapses on its own is unstable, leading to unlimited growth of synaptic strengths without additional homeostatic mechanisms. To control excitatory synaptic strengths we propose a novel form of synaptic plasticity at inhibitory synapses. We identify two key features of inhibitory plasticity, dominance of inhibition over excitation and a nonlinear dependence on the firing rate of postsynaptic excitatory neurons whereby inhibitory synaptic strengths change in the same direction as excitatory synaptic strengths. We demonstrate that the stable synaptic strengths realized by this novel inhibitory plasticity achieve a fixed excitatory/inhibitory set-point in agreement with experimental results. Applying a disinhibitory signal can gate plasticity and lead to the generation of receptive fields and strong bidirectional connectivity in a recurrent network. Hence, a novel form of nonlinear inhibitory plasticity can simultaneously stabilize excitatory synaptic strengths and enable learning upon disinhibition.
Genome-wide identification of the LexA-mediated DNA damage response inStreptomyces venezuelae
Authors: Stratton Kathryn J. , Bush Matthew J. , Chandra Govind , Stevenson Clare E. M. , Findlay Kim C. , Schlimpert Susan 
Published: March 2022

ABSTRACTDNA damage triggers a widely conserved stress response in bacteria called the SOS response that involves two key regulators, the activator RecA and the transcriptional repressor LexA. Despite the wide conservation of the SOS response, the number of genes controlled by LexA varies considerably between different organisms. The filamentous soil-dwelling bacteria of the genusStreptomycescontain LexA and RecA homologs but their roles inStreptomyceshave not been systematically studied. Here, we demonstrate that RecA and LexA are required for the survival ofStreptomyces venezuelaeduring DNA damaging conditions and for normal development during unperturbed growth. Monitoring the activity of a fluorescentrecApromoter fusion and LexA protein levels revealed that the activation of the SOS response is delayed inS. venezuelae. By combining global transcriptional profiling and ChIP-seq analysis, we determined the LexA regulon and defined the core set of DNA damage repair genes that are expressed in response to treatment with the DNA alkylating agent mitomycin C. Our results show that DNA damage-induced degradation of LexA results in the differential regulation of LexA target genes. Using Surface Plasmon Resonance, we further confirm the LexA DNA binding motif (SOS box) and demonstrate that LexA displays tight but distinct binding affinities to its target promoters, indicating a graded response to DNA damage.IMPORTANCEThe transcriptional regulator LexA functions as a repressor of the bacterial SOS response, which is induced during DNA damaging conditions. This results in the expression of genes important for survival and adaptation. Here, we report the regulatory network controlled by LexA in the filamentous antibiotic producingStreptomycesbacteria and establish the existence of the SOS response inStreptomyces. Collectively, our work reveals significant insights into the DNA damage response inStreptomycesthat will promote further studies to understand how these important bacteria adapt to their environment.
Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades
Authors: Jarrold Bradley B. , Ru Tan Christina Yan , Ho Chin Yee , Soon Ai Ling , Lam TuKiet T. , Yang Xiaojing , Nguyen Calvin , Guo Wei , Chew Yap Ching , DeAngelis Yvonne M. , Costello Lydia , De Los Santos Gomez Paola , Przyborski Stefan , Bellanger Sophie , Dreesen Oliver , Kimball Alexa B. , Oblong John E. 
Published: March 2022

ABSTRACTInflammaging is a theory of aging which purports that low-level chronic inflammation leads to cellular dysfunction and premature aging of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defense from the environment, particularly solar radiation. To better understand the impact of aging and photoexposure on epidermal biology we performed a systems biology-based analysis of photoexposed face and arm and photoprotected buttock sites from women between the ages of 20’s to 70’s. Biopsies were analyzed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss, and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic aging was accelerated. Genes associated with differentiation and senescence show increasing expression in the 30’s whereas genes associated with hypoxia and glycolysis increase in the 50’s. Proteomics comparing 60’s vs 20’s confirmed elevated levels of differentiation and glycolytic related proteins. Representative immunostaining for proteins of differentiation, senescence, and oxygen sensing/hypoxia shows similar relationships. This systems biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.
Age-related differences in functional network segregation in the context of sex and reproductive stage
Authors: Ballard Hannah K. , Jackson T. Bryan , Miller Abigail C. , Hicks Tracey H. , Bernard Jessica A. 
Published: March 2022

AbstractAge is accompanied by differences in the organization of functional brain networks, which impact behavior in adulthood. Functional networks tend to become less segregated and more integrated with age. However, sex differences in network segregation declines with age are not well-understood. Further, network segregation in the context of female reproductive stage is relatively understudied, though unmasking such relationships would be informative for elucidating biological mechanisms that contribute to sex-specific differences in aging. In the current work, we used data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) repository to evaluate differences in resting-state network segregation as a product of sex and reproductive stage. Reproductive stage was categorized using the Stages of Reproductive Aging Workshop (STRAW+10) criteria. Replicating prior work, we investigated the following functional networks: auditory, cerebellar-basal ganglia, cingulo-opercular task control, default mode, dorsal attention, fronto-parietal task control, salience, sensory somatomotor mouth, sensory somatomotor hand, ventral attention, and visual. First, our results mirror findings from previous work indicating that network segregation is lower with increasing age. Second, when analyzing associations between network segregation and age within each sex separately, we find differences between females and males. Finally, we report significant effects of reproductive stage on network segregation, though these findings are likely driven by age. Broadly, our results suggest that impacts of sex are important to evaluate when investigating network segregation differences across adulthood, though further work is needed to determine the unique role of menopause and sex hormones on the organization of functional brain networks within aging females.Key PointsSegregation of functional brain networks declines with increasing ageAge-segregation relationships are modified by biological sexReproductive stage may impact sex differences in brain network organization
A novel cis-element enabled bacterial uptake by plant cells
Authors: Cathebras Chloé , Gong Xiaoyun , Andrade Rosa Elena , Vondenhoff Ksenia , Keller Jean , Delaux Pierre-Marc , Hayashi Makoto , Griesmann Maximilian , Parniske Martin 
Published: March 2022

AbstractThe root nodule symbiosis (RNS) of plants with nitrogen-fixing bacteria is phylogenetically restricted to a single clade of flowering plants, which calls for yet unidentified trait acquisitions and genetic changes in the last common ancestor. Here we discovered – within the promoter of the transcription factor gene Nodule Inception (NIN) – a cis-regulatory element (PACE), exclusively present in members of this clade. PACE was essential for restoring infection threads (ITs) in nin mutants of the legume Lotus japonicus. PACE sequence variants from RNS-competent species appeared functionally equivalent. Evolutionary loss or mutation of PACE is associated with loss of this symbiosis. During early stages of nodule development, PACE dictates gene expression in a spatially restricted domain containing cortical cells carrying ITs. Consistent with its expression domain, PACE-driven NIN expression restored the formation of cortical ITs, also when engineered into the NIN promoter of tomato. Our data pinpoint PACE as a key evolutionary invention that connected NIN to a pre-existing symbiosis signal transduction cascade that governs the intracellular accommodation of arbuscular mycorrhiza fungi and is conserved throughout land plants. This connection enabled bacterial uptake into plant cells via intracellular support structures like ITs, a unique and unifying feature of this symbiosis.
Cells with Stochastically Increased Methyltransferase to Restriction Endonuclease Ratio Provide an Entry for Bacteriophage into Protected Cell Population
Authors: Kirillov Alexander , Morozova Natalia , Polinovaskaya Vasilisa , Smirnov Sergey , Khodorkovskii Mikhail , Zeng Lanying , Ispolatov Yaroslav , Severinov Konstantin 
Published: March 2022

ABSTRACTThe action of type II restriction-modification (RM) systems depends on restriction endonuclease (REase), which cleaves foreign DNA at specific sites, and methyltransferase (MTase), which protects host genome from restriction by methylating the same sites. We show that protection from phage infection increases as the copy number of plasmids carrying the Esp1396l RM system is increased. However, since increased plasmid copy number leads to both increased absolute intracellular REase and MTase levels and decreased MTase to REase ratio, it is impossible to determine which factor determines resistance/susceptibility to infection. By controlled expression of Esp1396I MTase or REase genes in cells carrying the Esp1396I system, we show that a shift in the MTase to REase ratio caused by overproduction of MTase or REase leads, respectively, to decreased or increased protection from infection. Consistently, due to stochastic variation of MTase and REase amount in individual cells, bacterial cells that are productively infected by bacteriophage have significantly higher MTase to REase ratios than cells that ward off the infection. Our results suggest that cells with transiently increased MTase to REase ratio at the time of infection serve as entry points for unmodified phage DNA into protected bacterial populations.