bluuebunny/crossref_metadata_2025_split huggingface dataset:
How best to co-deploy insecticides to minimise selection for resistance
Authors: Jones Sam , South Andy , Richardson Jason , Rees Sarah , Sherrard-Smith Ellie , Small Graham , Nimmo Derric , Hastings Ian 
Published: April 2023

AbstractInsecticides are widely used to control the insects that spread human infectious diseases, in particular falciparum malaria. This widespread use has driven insecticide resistance (IR) to high levels that may threaten the effectiveness of future control programmes. There is interest in identifying deployment methods that alleviate the pressures driving IR and we investigate three. Mixtures are, as already known, highly effective in slowing IR providing their effectiveness (ability to kill fully sensitive insects) remain close to 100%. Mixtures may be expensive and/or operationally difficult so two alternatives to mixtures were investigated. Panels, where different insecticides are physically closely adjacent, for examples, different panels on the same bednet; mosquitoes may therefore encounter both insecticides in the same foraging cycle. Micro-mosaics where different insecticides are deployed in slightly wider geographic proximity, for example in adjacent dwellings. The mosquitoes are unlikely to encountered both insecticides in the same foraging cycle but may encounter different insecticides in subsequent foraging. It is hoped that panels and/or micro-mosaics may, by allowing individual mosquitoes to potentially encounter both insecticides, be effective, lower-cost alternatives to mixtures. Our results suggest this is unlikely to be the case. When insecticides are fully effective then mixtures remain clearly the best strategy. As effectiveness falls then all three strategies are roughly equal. The operational decision of what deployment methods to use depends on how confident we are that insecticides will have high effectiveness that will be maintained in realistic field conditions post-deployment.
Rapid protein-protein interaction network creation from multiple sequence alignments with Deep Learning
Authors: Bryant Patrick , Noé Frank 
Published: April 2023

AbstractAlphaFold2 (AF) can evaluate protein-protein interactions (PPIs) with high accuracy by finding evolutionary signals between proteins but comes with a high computational cost. Here, we speed up the prediction with AF for PPI network prediction 40x and reduce the disk space requirements 4000x for a set of 1000 proteins. Our protocol is easy to install and freely available from:https://github.com/patrickbryant1/SpeedPPI.
Imbalanced expression of clustered protocadherins in pre- and post-synaptic compartments of CA1 pyramidal cells during hippocampal development
Authors: Tarusawa Etsuko , Hasegawa Saki , Noda Daisuke , Kawamura Nanami , Fukazawa Yugo , Watanabe Masahiko , Hirabayashi Takahiro , Yagi Takeshi 
Published: April 2023

SUMMARYClustered protocadherins (cPcdhs) are candidates for the neural circuit formation; however, the localization of cPcdhs in pre- and post-synaptic compartments has not been well characterized. Here we examined the localization of cPcdhγ proteins in the mouse hippocampal CA1 region using light and electron microscopy. From postnatal day 7 to 21, cPcdhγ immunosignals were detected in approximately 40–60% of spines of pyramidal cells. SDS-digested freeze-fracture replica labelling revealed that cPcdhγ immunolabeling was found in 50% of PSD 95-positive postsynaptic profiles but only in less than 10% of vGluT1-positive pre-synaptic terminals. Interestingly, cPcdhγ-positive pre-synaptic terminal was exclusively accompanied by cPcdhγ-positive postsynaptic counterpart. In addition, electrophysiological investigations revealed that the miniature excitatory postsynaptic current frequency in cPcdhγ cKO mice was significantly higher than that in wild-type mice. These results suggest that cPcdhγ proteins are unequally distributed in the pre- and post-synaptic membrane during neural circuit development and regulate the number of excitatory synapses.
SWI/SNF complex-mediated chromatin remodelling inCandida glabratais vital for immune evasion
Authors: Kumar Kundan , Pareek Aditi , Kaur Rupinder 
Published: April 2023

AbstractImmune evasion is critical for fungal virulence. However, how the human opportunistic pathogenCandida glabrata(Cg) accomplishes this is unknown. Here, using micrococcal nuclease-sequencing, RNA-sequencing, macrophage-signalling and genetic analyses, we demonstrate that chromatin reorganization in macrophage-internalizedCg, via CgSnf2 (ATPase subunit of the SWI/SNF chromatin remodelling complex), leads to upregulation and downregulation of immunosuppressive seven mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesinEPA1genes, respectively. Consistently,EPA1overexpression andCgMT-Cdeletion led to increased IL-1β (pro-inflammatory cytokine) production and reducedCgproliferation in macrophages. Further,CgSNF2deletion evoked increased IL-1β secretion, and the consequent killing of macrophage-internalizedCg, with elevated IL-1β levels being partially reversed in Akt-, p38-, NF-κB- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multipleCandidapathogens via NF-κB-dependent IL-1β production, underscoring NF-κB signalling’s role in fungal diseases. Finally, we present the first genome-wide nucleosome map of macrophage-internalizedCgconsisting of ∼12,000 dynamic and 70,000 total nucleosomes. Altogether, our findings directly link the nucleosome positioning-based chromatin remodelling to fungal immunomodulatory molecule expression, which dictatesCgfate in host immune cells.
Identification of merozoite secreted repertoire and immuno-pharmacological inhibition of a novel host-parasite interaction to block malarial infection
Authors: Singh Niharika , Munjal Akshay , Kumari Geeta , Kaushik Shikha , Kahlon Amandeep Kaur , Gupta Sakshi , Chaurasiya Ayushi , Anam Zill-e- , Maurya Mukesh Kumar , Srivastava Pallavi , Singhal Jhalak , Marothia Manisha , Joshi Prerna , Jain Ravi , Rex Devasahayam Arokia Balaya , Keshav Prasad T. S. , Mundae Manoj , Malhotra Pawan , Ranganathan Anand , Singh Shailja 
Published: April 2023

ABSTRACTBackgroundDuring the intra-erythrocytic proliferation ofPlasmodium falciparum, the host erythrocyte invasion is regarded as a complex and tightly regulated process comprising multiple receptor-ligand interactions, and numerous secretory molecules. Proteins secreted sequentially from apical organelles of merozoites serve as adhesins that play a crucial role in RBC invasion and can serve as vaccine and therapeutic targets.MethodsPurified merozoites were triggered to discharge apical organelle contents by exposure to ionic conditions mimicking that of blood plasma. The secreted proteins were subjected to tandem mass spectrometry, and a well-characterized invasion ligand, RhopH3, was identified. A novel RhopH3 receptor, 14-3-3□ was unearthed using a Bacterial two-hybrid approach. This interaction was confirmed using multiple biophysical and biochemical approaches. We were successful in disrupting this interaction using a de novo peptide binder of 14-3-3□, and we subsequently assessed its effect on merozoite invasion.ResultsA total of 66 proteins were identified in the secretory fraction with apical organellar or merozoite membrane localization. The well-known adhesin, RhopH3 was also identified and its interaction with the host phosphopeptide-binding protein, 14-3-3□ was established. We also discovered a de novo peptide with the potency to disrupt this crucial interaction, thereby blocking merozoite invasion.ConclusionWe, for the first time, report the secretory repertoire of plasmodium merozoite. Our study shows the importance of the erythrocyte protein, 14-3-3□ during the invasion process and paves the way for developing anti-malarial peptides or small molecules that inhibit the host-pathogen interaction, hence abrogating the invasion process.
Strong gene flow across an urbanised coastal landscape in a dune specialist digger wasp
Authors: Batsleer Femke , Duez Fabien , Maes Dirk , Bonte Dries 
Published: April 2023

AbstractContextGenetic connectivity is often disrupted by anthropogenic habitat fragmentation, and therefore often a focus in landscape-scale conservation. Landscape genetics methods allow for studying functional connectivity in heterogenous landscapes in detail and have the potential to inform conservation measures for a species’ regional persistence. Yet, for insects, functional connectivity through landscape genetics remains largely unexplored.ObjectivesWe aimed to assess the functional connectivity in the dune-specialist digger waspBembix rostrata, in a human-altered 15 km section along the Belgian coast, based on landscape genetics methods.MethodsWe optimised landscape resistance distances according to individual genetic distances with the package ResistanceGA. We combined this with a multi-model inference approach to deduce relative conductance or resistance of gene flow to natural and anthropogenic landscape types.ResultsOverall, the populations of this dune-specialist insect are genetically well-connected. We detected— on top of the prominent background process of isolation-by-distance—a weak but consistent signal of urban features facilitating gene flow.ConclusionsUrban areas are not a barrier to genetic connectivity of the dune-specialist insectB. rostratain the focal human-altered landscape. However, because urbanisation leads to larger scale fragmentation, its impact on the distribution of populations in the landscape and related effective regional gene flow remains substantial. As this species depends on early-succession dune vegetations, restoring and increasing sand dynamics at the local and landscape scale should be the focus of conservation aimed at the regional species’ persistence, rather than trying to increase habitat connectivity in this human-altered dune ecosystem.
CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers
Authors: Teh Selina Shiqing K. , Bowland Kirsten , Bennett Alexis , Halper-Stromberg Eitan , Skaist Alyza , Tang Jacqueline , Cai Fidel , Macoretta Antonella , Liang Hong , Kamiyama Hirohiko , Wheelan Sarah , Lin Ming-Tseh , Hruban Ralph H. , Scharpf Robert B. , Roberts Nicholas J. , Eshleman James R. 
Published: April 2023

AbstractSomatic mutations are desirable targets for selective elimination of cancer, yet most are found within the noncoding regions. We propose a novel, cancer-specific killing approach using CRISPR-Cas9 which exploits the requirement of a protospacer adjacent motif (PAM) for Cas9 activity. Through whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002), we identified an average of 417 somatic PAMs per tumor produced from single base substitutions. We analyzed 591 paired T-N samples from The International Cancer Genome Consortium and discovered medians of ∼455 somatic PAMs per tumor in pancreatic, ∼2800 in lung, and ∼3200 in esophageal cancer cohorts. Finally, we demonstrated >80% selective cell death of two targeted pancreatic cancer cell lines in co-cultures using 4-9 sgRNAs, targeting noncoding regions, designed from the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs through WGS.Statement of significanceThis study demonstrates the potential of CRISPR-Cas9 as a novel and selective anti-cancer strategy. It requires just a few targets to induce double strand breaks for significant cytotoxicity. Our findings markedly expand the repertoire of targetable mutations in cancers and support genetically targeting other adult solid tumor types.
Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes
Authors: Chang Yuan , Lusk Savannah , Chang Andersen , Ward Christopher S , Ray Russell S 
Published: April 2023

AbstractCentral noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS) and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. Therefore, we fully characterized the cumulative fate maps and acute adult expression patterns of all three Vesicular Glutamate Transporters (Slc17a7(Vglut1),Slc17a6(Vglut2), andSlc17a8(Vglut3)) in NA neurons, identifying a novel, dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the NA system. In contrast to our initial hypothesis that NA derived glutamate is required to breathing, our functional studies showed that loss of Vglut2 throughout the NA system failed to alter breathing or metabolism under room air, hypercapnia, or hypoxia in unrestrained and unanesthetized mice. These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes. These outcomes challenge the current understanding of central NA neurons in the control of breathing and suggests that glutamate may not be a critical target to understand NA neuron dysfunction in respiratory diseases.
Complex spikes perturb movements, revealing the sensorimotor map of Purkinje cells
Authors: Muller Salomon Z. , Pi Jay S. , Hage Paul , Fakharian Mohammad Amin , Sedaghat-Nejad Ehsan , Shadmehr Reza 
Published: April 2023

AbstractThe cerebellar cortex performs computations that are critical for control of our actions, and then transmits that information via simple spikes of Purkinje cells (P-cells) to downstream structures. However, because P-cells are many synapses away from muscles, we do not know how their output affects behavior. Furthermore, we do not know the level of abstraction, i.e., the coordinate system of the P-cell’s output. Here, we recorded spiking activities of hundreds of P-cells in the oculomotor vermis of marmosets during saccadic eye movements and found that following the presentation of a visual stimulus, the olivary input to a P-cell encoded a probabilistic signal that coarsely described both the direction and the amplitude of that stimulus. When this input was present, the resulting complex spike briefly suppressed the P-cell’s simple spikes, disrupting the P-cell’s output during that saccade. Remarkably, this brief suppression altered the saccade’s trajectory by pulling the eyes toward the part of the visual space that was preferentially encoded by the olivary input to that P-cell. Thus, analysis of behavior in the milliseconds following a complex spike unmasked how the P-cell’s output influenced behavior: the preferred location in the coordinates of the visual system as conveyed probabilistically from the inferior olive to a P-cell defined the action in the coordinates of the motor system for which that P-cell’s simple spikes directed behavior.SignificanceWe lack general principles that can describe how changes in a P-cell’s simple spikes might alter behavior. Here, we show that a brief suppression of a P-cell’s simple spikes in the oculomotor vermis consistently pulls the eyes in a direction that corresponds to the preferred location of the sensory space as conveyed probabilistically to that P-cell from the inferior olive. Thus, the inferior olive defines the coordinate system regarding the information that a P-cell is providing to the rest of the brain.
Comparative population genomics provide new insight into the evolutionary history and adaptive potential of World Ocean krill
Authors: Choquet Marvin , Lenner Felix , Cocco Arianna , Toullec Gaëlle , Corre Erwan , Toullec Jean-Yves , Wallberg Andreas 
Published: April 2023

AbstractGenetic variation is instrumental for adaptation to new or changing environments but it is poorly understood how it is structured and contributes to adaptation in pelagic species without clear barriers to gene flow. Here we use extensive transcriptome datasets from 20 krill species collected across the Atlantic, Indian, Pacific and Southern Oceans and compare genetic variation both within and between species across thousands of genes. We resolve phylogenetic interrelationships and uncover genomic evidence in support of elevating the crypticEuphausia similisvar.armatainto species. We estimate levels of genetic variation and rates of adaptive protein evolution among species and find that these are comparably low in large Southern Ocean species endemic to cold environments, including the Antarctic krillEuphausia superba, suggesting their adaptive potential to rapid climate change may also be low. We uncover hundreds of candidate loci with signatures of adaptive divergence between krill native to cold and warm waters and identify candidates for cold-adaptation that have also been detected in Antarctic fish, including genes that govern thermal reception such asTrpA1. Our results suggest parallel genetic responses to similar selection pressures across Antarctic taxa and provide new insights into the adaptive potential of important zooplankton that are already strongly affected by climate change.
Cue-driven microbial cooperation and communication: evolving quorum sensing with honest signalling
Authors: Czárán Tamás , Scheuring István , Zachar István , Számadó Szabolcs 
Published: April 2023

AbstractBackgroundQuorum sensing (QS) is the ability of microorganisms to assess local clonal density by measuring the extracellular concentration of signal molecules that they produce and excrete. QS is also the only known way of bacterial communication that supports the coordination of within-clone cooperative actions requiring a certain threshold density of cooperating cells. Cooperation aided by QS communication is sensitive to cheating in two different ways:laggardsmay benefit from not investing in cooperation but enjoying the benefit provided by their cooperating neighbors, whereasLiarsexplicitly promise cooperation but fail to do so, thereby convincing potential cooperating neighbors to help them, for almost free. Given this double vulnerability to cheats, it is not trivial why QS-supported cooperation is so widespread among prokaryotes.ResultsWe investigated the evolutionary dynamics of QS in populations of cooperators for whom the QS signal is an inevitable side effect of producing the public good itself (cue-based QS). Using spatially explicit agent-based lattice simulations of QS-aided threshold cooperation (whereby cooperation is effective only above a critical cumulative level of contributions) and three different (analytical and numerical) approximations of the lattice model we explored the dynamics of QS-aided threshold cooperation under a feasible range of parameter values. We demonstrate three major advantages of cue-driven cooperation. First, laggards cannot wipe out cooperation under a wide range of reasonable environmental conditions, in spite of an unconstrained possibility to mutate to cheating; in fact, cooperators may even exclude laggards at high cooperation thresholds. Second, lying almost never pays off, if the signal is an inevitable byproduct (i.e., the cue) of cooperation; even very cheap fake signals are selected against. And thirdly, QS is most useful if local cooperator densities are the least predictable, i.e., if their lattice-wise mean is close to the cooperation threshold with a substantial variance.ConclusionsComparing the results of the four different modelling approaches indicates that cue-driven threshold cooperation may be a viable evolutionary strategy for microbes that cannot keep track of past behavior of their potential cooperating partners, in spatially viscous and in well-mixed environments alike.
Driving and suppressing the human language network using large language models
Authors: Tuckute Greta , Sathe Aalok , Srikant Shashank , Taliaferro Maya , Wang Mingye , Schrimpf Martin , Kay Kendrick , Fedorenko Evelina 
Published: April 2023

AbstractTransformer models such as GPT generate human-like language and are highly predictive of human brain responses to language. Here, using fMRI-measured brain responses to 1,000 diverse sentences, we first show that a GPT-based encoding model can predict the magnitude of brain response associated with each sentence. Then, we use the model to identify new sentences that are predicted to drive or suppress responses in the human language network. We show that these model-selected novel sentences indeed strongly drive and suppress activity of human language areas in new individuals. A systematic analysis of the model-selected sentences reveals that surprisal and well-formedness of linguistic input are key determinants of response strength in the language network. These results establish the ability of neural network models to not only mimic human language but also noninvasively control neural activity in higher-level cortical areas, like the language network.
Pronoun resolution via reinstatement of referent-related activity in the delta band
Authors: Ding Rong , Oever Sanne ten , Martin Andrea E. 
Published: April 2023

AbstractHuman language offers a variety of ways to create meaning, one of which is referring to entities, objects, or events in the world. One such meaning maker is understanding to whom or to what a pronoun in a discourse refers to. To understand a pronoun, the brain must access matching entities or concepts that have been encoded in memory from previous linguistic context. Models of language processing propose that internally stored linguistic concepts, accessed via exogenous cues such as phonological input of a word, are represented as (a)synchronous activities across a population of neurons active at specific frequency bands. Converging evidence suggests that delta band activity (1-3Hz) is involved in temporal and representational integration during sentence processing. Moreover, recent advances in the neurobiology of memory suggest that recollection engages reinstatement of neural dynamics that occurred during memory encoding. Integrating from these two research lines, we here predicted that neural dynamic patterns, especially in delta frequency range, underlying referential meaning representation would be reinstated during pronoun resolution. By leveraging neural decoding techniques (i.e., representation similarity analysis) on a magnetoencephalogram (MEG) dataset acquired during a naturalistic story-listening task, we provide evidence that delta-band activity underlies referential meaning representation. Our findings suggest that, during spoken language comprehension, endogenous linguistic representations such as referential concepts may be retrieved and represented via reinstatement of dynamic neural patterns.