bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study stratified byMAPThaplotypes identifies potential novel loci in Parkinson’s disease
Authors: Senkevich Konstantin , Bandres-Ciga Sara , Cisterna-García Alejandro , Yu Eric , Bustos Bernabe I. , Krohn Lynne , Lubbe Steven J. , Botía Juan A. ,   the International Parkinson’s Disease Genomics Consortium (IPDGC), Gan-Or Ziv
Published: April 2023

Objective

To identify genetic factors that may modify the effects of theMAPTlocus in Parkinson’s disease (PD).

Methods

We used data from the International Parkinson’s Disease Genomics Consortium (IPDGC) and the UK biobank (UKBB). We stratified the IPDGC cohort for carriers of the H1/H1 genotype (PD patients n=8,492 and controls n=6,765) and carriers of the H2 haplotype (with either H1/H2 or H2/H2 genotypes, patients n=4,779 and controls n=4,849) to perform genome-wide association studies (GWASs). Then, we performed replication analyses in the UKBB data. To study the association of rare variants in the new nominated genes, we performed burden analyses in two cohorts (Accelerating Medicines Partnership – Parkinson Disease and UKBB) with a total sample size PD patients n=2,943 and controls n=18,486.

Results

We identified a novel locus associated with PD amongMAPTH1/H1 carriers nearEMP1(rs56312722, OR=0.88, 95%CI= 0.84-0.92, p= 1.80E-08), and a novel locus associated with PD amongMAPTH2 carriers nearVANGL1(rs11590278, OR=1.69 95%CI=1.40-2.03, p= 2.72E-08). Similar analysis of the UKBB data did not replicate these results and rs11590278 nearVANGL1did have similar effect size and direction in carriers of H2 haplotype, albeit not statistically significant (OR= 1.32, 95%CI= 0.94-1.86, p=0.17). RareEMP1variants with high CADD scores were associated with PD in theMAPTH2 stratified analysis (p=9.46E-05), mainly driven by the p.V11G variant.

Interpretation

We identified several loci potentially associated with PD stratified byMAPThaplotype and larger replication studies are required to confirm these associations.
Cross-cohort mixture analysis: a data integration approach with applications on gestational age and DNA-methylation-derived gestational age acceleration metrics
Authors: Colicino Elena , Ascari Roberto , Saddiki Hachem , Merced-Nieves Francheska , Pedretti Nicolo Foppa , Huddleston Kathi , Wright Robert O , Wright Rosalind J , Outcomes Child Health
Published: April 2023

Background

Data integration of multiple epidemiologic studies can provide enhanced exposure contrast and statistical power to examine associations between environmental exposure mixtures and health outcomes. Extant studies have combined population studies and identified an overall mixture-outcome association, without accounting for differences across studies.

Objective

To extend the novel Bayesian Weighted Quantile Sum (BWQS) regression to a hierarchical framework to analyze mixtures across multiple cohorts of different sample sizes.

Methods

We implemented a hierarchical BWQS (HBWQS) approach that (i) aggregates sample size of multiple cohorts to calculate an overall mixture index, thereby identifying the most harmful exposure(s) across cohorts; and (ii) provides cohort-specific associations between the overall mixture index and the outcome. We showed results from six simulated scenarios including four mixture components in five and ten populations, and two real case-examples on the association between prenatal metal mixture exposure—comprising arsenic, cadmium and lead—and both gestational age and gestational age acceleration metrics.

Results

Results from simulated scenarios showed good empirical coverage and little bias for all parameters estimated with HBWQS. The Watanabe-Akaike information criterion (WAIC) for the HBWQS regression showed a better average performance across scenarios than the BWQS regression. HBWQS results incorporating cohorts within the national Environmental influences on Child Health Outcomes (ECHO) program from three different sites (Boston, New York City (NYC), and Virginia) showed that the environmental mixture—composed of low levels of arsenic, cadmium, and lead—was negatively associated with gestational age in NYC..

Conclusions

This novel statistical approach facilitates the combination of multiple cohorts and accounts for individual cohort differences in mixture analyses. Findings from this approach can be used to develop regulations, policies, and interventions regarding multiple co-occurring environmental exposures and it will maximize use of extant publicly available data.
Loss of Mitochondrial Enoyl CoA Reductase causes elevated ceramide levels and impairs iron metabolism
Authors: Dutta Debdeep , Kanca Oguz , Byeon Seul Kee , Marcogliese Paul C. , Zuo Zhongyuan , Shridharan Rishi V. , Park Jun Hyoung ,   Undiagnosed Diseases Network, Lin Guang , Ge Ming , Heimer Gali , Kohler Jennefer N. , Wheeler Matthew T. , Kaipparettu Benny A. , Pandey Akhilesh , Bellen Hugo J.
Published: April 2023

In most eukaryotic cells fatty acid synthesis occurs in the cytoplasm as well as in mitochondria. However, the relative contribution of mitochondrial fatty acid synthesis (mtFAS) to the cellular lipidome of metazoans is ill-defined. Hence, we studied the function of the fly Mitochondria enoyl CoA reductase (Mecr), the enzyme required for the last step of mtFAS. Loss ofmecrcauses lethality while neuronal loss leads to progressive neurological defects. We observe an elevated level of ceramides, a defect in Fe-S cluster biogenesis and increased iron levels inmecrmutants. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes indicating that increased ceramides and iron metabolism are interrelated and play an important role in the pathogenesis. Mutations in humanMECRcause pediatric-onset neurodegeneration and patient-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study shows an as-yet-unidentified role ofmecr/MECRin ceramide and iron metabolism providing a mechanistic link between mtFAS and neurodegeneration.
Grazing hinders seed dispersal during crop failure in a declining oak woodland
Authors: Vaz Pedro G. , Bugalho Miguel N. , Fedriani Jose M.
Published: April 2023

Masting, the synchronized production of variable quantities of seeds, occurs in many grazed systems and can be interspersed with years of extreme crop failure, whose frequency and unpredictability are increasing with climate change. Yet, the combined impact of crop failure and grazing on seed dispersal and seed-to-seedling transition remains poorly understood. To address this concern, we investigated rodent-mediated cork-oak (Quercus suber) acorn predation, dispersal, and seedling emergence in cattle grazed and non-grazed areas in central Portugal during years with contrasting masting seasons. We found that extreme crop failure led to six times longer and faster acorn dispersal, with 83% more dispersal events than during a year of reproductive success. The percentage of predated acorns also increased by 84%. However, the higher acorn predation was offset by a 2.4-fold higher percentage of unpredated dispersed acorns recruiting into seedlings. Both years ended up recruiting a similar number of seedlings. Acorns emerged seedlings 3.4 times farther in the crop failure year than in the crop success year. Cattle grazing was the main constraint on seed dispersal distance, reducing it by 51% during the extreme crop failure year, while having no noticeable effect during the successful crop year. Our study provides empirical evidence that cattle grazing modulates how an extreme crop failure year can surprisingly be an opportunity for trees remaining fecund to have seedlings established farther apart than in a crop success year. If we are to better manage and preserve the high conservation and socio-economic value of Mediterranean cork oak woodlands in the face of climate change, we must prioritize fecund trees and carefully manage seed dispersal factors such as cattle grazing, particularly during years of crop failure.
Myosin inhibitor reverses hypertrophic cardiomyopathy in pediatric iPSC-cardiomyocytes to mirror variant correction
Authors: Kinnear Caroline , Said Abdelrahman , Meng Guoliang , Zhao Yimu , Wang Erika Y , Parmar Neha , Wei Wei , Billia Filio , Simmons Craig A , Radisic Milica , Ellis James , Mital Seema
Published: April 2023

Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomere gene variants in MYH7 and MYBPC3. Targeted drugs like myosin ATPase inhibitors have shown efficacy in adult HCM but have not been evaluated in children. We generated iPSC-cardiomyocytes (CMs) from four children with HCM harboring variants inMYH7(V606M; R453C)orMYBPC3 (G148R; P955fs and TNNI3_A157P), variant-corrected controls, and a healthy individual. All CMs showed hypertrophy and sarcomere disorganization. All 3 single variant CMs showed higher contractility, slower relaxation, higher calcium transients and higher ATPase activity. OnlyMYH7variant CMs showed stronger myosin-actinin binding. Targeted myosin ATPase inhibitor showed complete rescue of the phenotype in affected CMs and in cardiac Biowires to mirror isogenic controls. The response was stronger compared to verapamil or metoprolol, highlighting the need for clinical trials of myosin targeted therapy in pediatric HCM patients. The phenotype and response to drug therapy are influenced by the underlying genotype.
Reprogramming a high robustGeobacillus thermoglucosidasiusfor efficient synthesis of polymer-grade lactic acid under extremely high temperature (60°C)
Authors: Liu Jiongqin , Han Xiao , Tao Fei , Xu Ping
Published: April 2023

Optically pure lactic acid is an important precursor for the synthesis of biodegradable plastic polylactic acid.Geobacillus thermoglucosidasiusis a thermophilic bacterial chassis with industrial potential. In this study, we reprogrammed this chassis to efficiently produce polymer-grade lactic acid by combining rational and semi-rational design strategies. We obtained optically pure L-lactic acid- and D-lactic acid-producing strains, GTD17 and GTD7, respectively, via rational strategies: constructing a lactic acid synthesis module, deleting by-product synthesis, and enhancing lactic acid production. At an extremely high temperature (60°C), the engineered strain GTD17 produced 94.2 g L−1of L-lactic acid with an overall yield and productivity of 91.5% and 2.0 g L−1h−1, respectively, and the optical purity of L-lactic acid was 99.5%. We then performed semi-rational adaptive evolution on the engineered strain GTD7 to obtain an optically pure D-lactic acid-producing strain GTD7-144; at the extremely high temperature (60°C), it produced 153.1 g L−1of D-lactic acid with an overall yield and productivity of 93.0% and 3.2 g L−1h−1, respectively. The optical purity of the D-lactic acid was 99.6%. Genome resequencing and analysis of the strain GTD7-144 revealed potential genetic targets that may improve production performance. This study represents an advancement in the high-temperature production of polymer-grade lactic acid byG. thermoglucosidasius.
Osmolar modulation drives reversible cell cycle exit and human pluripotent cell differentiation via NF-κВ and WNT signaling
Authors: Chui Jonathan Sai-Hong , Izuel-Idoype Teresa , Qualizza Alessandra , Pires de Almeida Rita , van der Veer Bernard K. , Vanmarcke Gert , Athanasouli Paraskevi , Boon Ruben , Vriens Joris , Koh Kian Peng , Grunsven Leo van , Verfaillie Catherine M. , Lluis Frederic
Published: April 2023

Terminally differentiated cells are regarded as the most stable and common cell state in adult organisms as they reside in growth arrest and carry out their cellular function. Improving our understanding of the mechanisms involved in promoting cell cycle exit would facilitate our ability to manipulate pluripotent cells into mature tissues for both pharmacological and therapeutic use. Here, we demonstrated that a hyperosmolar environment enforced a protective p53-independent quiescent state in dedifferentiated hepatoma cells and pluripotent stem cells (PSCs)-derived models of human hepatocytes and endothelial cells, representing the endodermal and mesodermal lineages. Prolonged culture in hyperosmolar conditions stimulated transcriptional and functional cell maturation. Interestingly, hyperosmolar conditions did not only trigger cell cycle exit and cellular maturation but were also necessary to maintain this maturated state, as switching back to plasma osmolarity caused the loss of maturation markers and the gain of proliferative markers. Transcriptome analysis revealed activation of NF-κВ and repression of WNT signaling as the two main pathways downstream of osmolarity-regulated growth arrest and cell maturation, respectively. This study revealed that increased osmolarity serves as a biochemical signal to promote long-term growth arrest, transcriptional changes, and maturation into different lineages, serving as a practical method to generate differentiated hiPSCs that resemble their mature counterpart more closely.
Never judge a bird by its feathers: genetics unveils the true target of trafficking in morphologically similarCopsychusspecies
Authors: Cavill Emily L. , Hernández-Alonso Germán , Ogden Rob , Gilbert M. Thomas. P.
Published: April 2023

Trends in wildlife crime continue to rise and contribute to the ongoing decline of our planet’s biodiversity. We applied a genetic approach to ascertain the geographic origin of a suspected Seychelles Magpie-robin confiscated in Singapore during international transit, and to confirm illegal trade of this species. However, mitochondrial analyses revealed this individual to be a subspecies of Oriental Magpie-robin, endemic to the island of Borneo, and bearing similar morphology to the Seychelles species. We thus consider the implications of correct species identification on captive care and repatriation in cases of wildlife confiscation, and emphasise the value of using genetics in wildlife crime investigation.
Fast and flexible joint fine-mapping of multiple traits via the Sum of Single Effects model
Authors: Zou Yuxin , Carbonetto Peter , Xie Dongyue , Wang Gao , Stephens Matthew
Published: April 2023

We introduce mvSuSiE, a multi-trait fine-mapping method for identifying putative causal variants from genetic association data (individual-level or summary data). mvSuSiE learns patterns of shared genetic effects from data, and exploits these patterns to improve power to identify causal SNPs. Comparisons on simulated data show that mvSuSiE is competitive in speed, power and precision with existing multi-trait methods, and uniformly improves on single-trait fine-mapping (SuSiE) in each trait separately. We applied mvSuSiE to jointly fine-map 16 blood cell traits using data from the UK Biobank. By jointly analyzing the traits and modeling heterogeneous effect sharing patterns, we discovered a much larger number of causal SNPs (>3,000) compared with single-trait fine-mapping, and with narrower credible sets. mvSuSiE also more comprehensively characterized the ways in which the genetic variants affect one or more blood cell traits; 68% of causal SNPs showed significant effects in more than one blood cell type.
SINGLE CELL RESOLUTION OF THE ADULT ZEBRAFISH INTESTINE UNDER CONVENTIONAL CONDITIONS, AND IN RESPONSE TO AN ACUTEVIBRIO CHOLERAEINFECTION
Authors: Jones Lena O. , Willms Reegan J. , Eklund Mckenna , Graham Ralph Derrick V. , Xu Xinyue , Shin Minjeong , Foley Edan
Published: April 2023

Vibrio choleraeis an aquatic bacterium that primarily infects the gastrointestinal tract, causing the severe and potentially deadly diarrheal disease, cholera. Despite the impact ofVibrioon global health, our understanding of host mucosal responses to the pathogen at the site of infection remains limited, highlighting a critical knowledge gap that must be addressed to develop more effective prevention and treatment strategies. Using a natural infection model, we combined physiological and single-cell transcriptomic studies to characterize adult zebrafish guts raised under conventional conditions and after a challenge withVibrio. We discovered thatVibriocauses a mild mucosal immune response characterized by T cell activation and enhanced antigen capture in the epithelium. Additionally, we discovered thatVibriosuppresses host interferon signaling, and that ectopic activation of interferon significantly alters the course of infection. Notably, we also found that the adult zebrafish gut shares many similarities with mammalian counterparts, including the presence of previously undescribed Best4+ cells, tuft cells, and a population of basal cycling cells. These discoveries provide important insights into host-pathogen interactions and emphasize the utility of zebrafish as a natural model ofVibrioinfection.
Ribosomal L12 stalks recruit elongation factors to speed protein synthesis inEscherichia coli
Authors: Hofmann Jennifer L. , Yang Theodore S. , Sunol Alp M. , Zia Roseanna N.
Published: April 2023

Actively translating ribosomes must wait after each elongation step for a new ternary complex (EF-Tu·aa-tRNA·GTP) to be delivered, facilitating rapid codon recognition testing and continued elongation. We recently showed that this wait time rate-limits elongation inEscherichia colidue to a competitive combinatoric search through crowded cytoplasm by thousands ofE. coli’s 42 unique ternary complexes. Here, we investigate whether L12 subunits on ribosomes’ surfaces pool translation molecules to reduce this wait time. To do so, we mimic elongation transport and reactions in a physiologically accurate, physics-based model of crowdedE. colicytoplasm. We find that L12 pre-loading as much as doubles translation rate by optimizing sampling of novel ternary complexes. But more L12 is not always better: faster-growing bacteria tend to have fewer L12. We resolve this paradox by demonstrating a tradeoff between binding and novel sampling as a function of copy number inE. coli. Variable L12 copy numbers may thus have evolved for fast or slow bacterial growth as complementary survival strategies.
Abundance of Oligoflexales bacteria is associated with algal symbiont density independent of thermal stress in Aiptasia anemones
Authors: Aguirre Emily G. , Fine Marissa J. , Kenkel Carly D.
Published: April 2023

Many multicellular organisms, such as humans, plants, and invertebrates, depend on symbioses with microbes for metabolic cooperation and exchange. Reef-building corals, an ecologically important order of invertebrates, are particularly vulnerable to environmental stress in part because of their nutritive symbiosis with dinoflagellate algae, and yet also benefit from these and other microbial associations. While coral microbiomes remain difficult to study because of their complexity, the anemone Aiptasia is emerging as a simplified model. Research has demonstrated co-occurrences between microbiome composition and the abundance and type of algal symbionts in cnidarians. However, whether these patterns are the result of general stress-induced shifts or depletions of algal-associated bacteria remains unclear. Our study aimed to distinguish the effect of changes in symbiont density and thermal stress on the microbiome of symbiotic Aiptasia strain CC7 by comparing them with aposymbiotic anemones, depleted of their native symbiont,Symbiodinium linucheae. Our analysis indicated that overall, thermal stress had the greatest impact on disrupting the microbiome. We found that three bacterial classes made up most of the relative abundance (60-85 %) in all samples, but the rare microbiome fluctuated between symbiotic states and following thermal stress. We also observed thatS. linucheaedensity correlated with abundance of Oligoflexales, suggesting these bacteria may be primary symbionts of the dinoflagellate algae. The findings of this study help expand knowledge on prospective multipartite symbioses in the cnidarian holobiont and how they respond to environmental disturbance.
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

Insecticides 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

AlphaFold2 (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

Clustered 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

Immune 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

Background

During 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.

Methods

Purified 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.

Results

A 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.

Conclusion

We, 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

Context

Genetic 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.

Objectives

We 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.

Methods

We 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.

Results

Overall, 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.

Conclusions

Urban 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

Somatic 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 significance

This 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

Central 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.
Higher Precision in Initial rates may be achievable: A test of a Pseudo-statistical method
Authors: Udema Ikechukwu
Published: April 2023

Background: There has been a concerted effort at establishing the best method for the measurement of initial rates for various purposes, including the calculation of kinetic parameters, the maximum velocity (Vmax), and the Michaelis-Menten constant (KM). Objectives: The objectives of this research are: 1) to derive equations without KM for the determination of the Vmax in particular and vice versa; 2) to determine the KM and Vmax with other equations other than the Michaelian equation; and 3) to subject the calculated and extrapolated kinetic parameters to pseudo-statistical remediation where necessary as a test of their viability and usefulness. Methods: The study was experimental and theoretical. It is supported by the Bernfeld method of enzyme assay. Result: By graphical means, the Vmax and KM values for galactosidase respectively range between 163 and 185 microM/min and between 2.07 and 2.77 mg/L; the range by calculations is 177 and 214 micro M/min and 2.45 and 3.311 mg/L, subject to pseudo-statistical remediation. Overall, the ranges of Vmax and KM values for alpha-amylase from both the graphical method and calculation are, respectively, 1.095 to 1.018 mM/min and 18.15 to 20.554 g/L. Conclusion: The equations for the determination of the KM and Vmax, which are respectively invariant with respect to each other, were rederived. The initial rates must not be a mixture of both if the true KM and Vmax are of interest. The new pseudo-statistical method for the remediation of error in all measurements, if necessary, is viable, useful, and robust.
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

The 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.

Significance

We 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

Abstract

Genetic 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

Background

Quorum 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.

Results

We 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.

Conclusions

Comparing 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

Transformer 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

Human 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.
Staying in control: characterising the mechanisms underlying cognitive control in high and low arousal states
Authors: Alameda Clara , Avancini Chiara , Sanabria Daniel , Bekinschtein Tristan A. , Canales-Johnson Andrés , Ciria Luis F.
Published: April 2023

Throughout the day, humans show natural fluctuations in arousal that impact cognitive function. To study the behavioural dynamics of cognitive control during high and low arousal states, healthy participants performed an auditory conflict task during high-intensity physical exercise (N= 39) or drowsiness (N= 33). In line with the pre-registered hypotheses, conflict and conflict adaptation effects were preserved during both altered arousal states. Overall task performance was markedly poorer during low arousal, but not for high arousal. Modelling behavioural dynamics with drift-diffusion analysis revealed evidence accumulation and non-decision time decelerated, and decisional boundaries became wider during low arousal, whereas high arousal was unexpectedly associated with a decrease in the interference of task-irrelevant information processing. These findings show how arousal differentially modulates cognitive control at both sides of normal alertness, and further validates drowsiness and physical exercise as key experimental models to disentangle the interaction between physiological fluctuations on cognitive dynamics.
Integrin β4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1
Authors: Fang Huan , Ren Wenlong , Cui Qiuxia , Liang Huichun , Yang Chuanyu , Liu Wenjing , Wang Xinye , Liu Xue , Shi Yujie , Feng Jing , Chen Ceshi
Published: April 2023

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote triple-negative breast cancer cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin β4. Integrin β4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in triple-negative breast cancer. These results indicate that the Integrin β4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in triple-negative breast cancer.