bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isotope analysis of birds’ eye lens provides early-life information
Authors: Hasegawa Emi Arai , Matsubayashi Jun , Tayasu Ichiro , Goto Tatsuhiko , Inoue Haruka , Rossberg Axel G. , Yoshimizu Chikage , Hasegawa Masaru , Akasaka Takumi 
Published: August 2024

AbstractEarly-life environment has a long-lasting effect on later life, though its estimation is often prevented in the wild because of a lack of available methods. Recently, isotope analysis of eye lenses has attracted considerable interest as a means to reconstruct the environmental conditions experienced by animals during the developmental period. This analysis has mostly been confined to fish for practical reasons and remains to be resolved for application to other animals. In this study, we broadened its applicability by developing a novel approach and verifying its usability for the reconstruction of early-life environments. We performed a feeding experiment using Japanese quail (Coturnix japonica), in which we administered two diets: one composed mainly of C3 plants (lowδ13C and highδ15N) and the other of C4 plants (highδ13C and lowδ15N). Quails in the control group were continuously fed a C3-based diet from hatching until 200 days old, whereas those in the treatment groups (T10, T15, T20, and T40) were switched from the C3 to the C4-based diet at 10, 15, 20, and 40 days after hatching, respectively. We found that theδ13C in the eye lenses of the treatment groups decreased from the center layer to the middle layer of the lens and then increased toward the outer layer, thus reflecting the diet change. In contrast, those of the control group exhibited a decreasing trend and equilibrated at the middle layer of the eye lens, with no increase thereafter. This novel approach revealed the postnatal feeding histories of the diet-shift experiment. The highδ13C values observed in the center of the eye lenses would reflect the prenatal feeding environment, i.e., the C4-based diet consumed by their mothers, which is further reinforced by higherδ15N values at this position due to the consumption of egg yolk-derived nutrition. These results indicate that the avian eye lens can be used as an “isotopic chronicle,” which is a useful tool for reconstructing chronological isotopic information about their early-life history.
Brain Charts for the Rhesus Macaque Lifespan
Authors: Alldritt S. , Ramirez J.S.B. , Vos de Wael R. , Bethlehem R. , Seidlitz J. , Wang Z. , Nenning K. , Esper N.B. , Smallwood J. , Franco A.R. , Byeon K. , Alexander-Bloch A. , Amaral D.G. , Amiez C. , Balezeau F. , Baxter M.G. , Becker G. , Bennett J. , Berkner O. , Blezer E.L.A. , Brambrink A.M. , Brochier T. , Butler B. , Campos L.J. , Canet-Soulas E. , Chalet L. , Chen A. , Cléry J. , Constantinidis C. , Cook D.J. , Dehaene S. , Dorfschmidt L. , Drzewiecki C.M. , Erdman J.W. , Everling S. , Falchier A. , Fleysher L. , Fox A. , Freiwald W. , Froesel M. , Froudist-Walsh S. , Fudge J. , Funck T. , Gacoin M. , Gale D.J. , Gallivan J. , Garin C.M. , Griffiths T.D. , Guedj C. , Hadj-Bouziane F. , Hamed S.B. , Harel N. , Hartig R. , Hiba B. , Howell B.R. , Jarraya B. , Jung B. , Kalin N. , Karpf J. , Kastner S. , Klink C. , Kovacs-Balint Z.A. , Kroenke C. , Kuchan M.J. , Kwok S.C. , Lala K.N. , Leopold D.A. , Li G. , Lindenfors P. , Linn G. , Mars R.B. , Masiello K. , Menon R.S. , Messinger A. , Meunier M. , Mok K. , Morrison J.H. , Nacef J. , Nagy J. , Neudecker V. , Neuringer M. , Noonan M.P. , Ortiz-Rios M. , Perez-Zoghbi J.F. , Petkov C.I. , Pinsk M. , Poirier C. , Procyk E. , Rajimehr R. , Reader S.M. , Rudko D.A. , Rushworth M.F.S. , Russ B.E. , Sallet J. , Sanchez M.M. , Schmid M.C. , Schwiedrzik C.M. , Scott J.A. , Sein J. , Sharma K.K. , Shmuel A. , Styner M. , Sullivan E.L. , Thiele A. , Todorov O.S. , Tsao D. , Tusche A. , Vlasova R. , Wang Z. , Wang L. , Wang J. , Weiss A.R. , Wilson C.R.E. , Yacoub E. , Zarco W. , Zhou Y. , Zhu J. , Margulies D. , Fair D. , Schroeder C. , Milham M. , Xu T. 
Published: August 2024

AbstractRecent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.
Systematic evaluation ofde novomutation calling tools using whole genome sequencing data
Authors: Shah Anushi , Monger Steven , Troup Michael , Ip Eddie KK , Giannoulatou Eleni 
Published: August 2024

ABSTRACTDe novomutations (DNMs) are genetic alterations that occur for the first time in an offspring. DNMs have been found to be a significant cause of severe developmental disorders. With the widespread use of next-generation sequencing (NGS) technologies, accurate detection of DNMs is crucial. Several bioinformatics tools have been developed to call DNMs from NGS data, but no study to date has systematically compared these tools. We used both real whole genome sequencing (WGS) data from a trio from the 1000 Genomes Project (1000G) and simulated trio data to evaluate four DNM calling tools: DeNovoGear, TrioDeNovo, PhaseByTransmission, and VarScan 2. For DNMs called in the real dataset, we observed 8.7% concordance between all tools, while up to 36.2% of DNMs were unique to each caller. For simulated trio WGS datasets spiked with 100 DNMs, the concordance rate was also low at 4.1%. DeNovoGear achieved the highest F1-score on both the real and simulated datasets. Our study provides valuable recommendations for the selection and application of DNM callers on WGS trio data.
Efficient molecular mendelian randomization screens with LaScaMolMR.jl
Authors: Mathieu Samuel , Minvielle Moncla Louis-Hippolyte , Briend Mewen , Duclos Valentine , Rufiange Anne , Bossé Yohan , Mathieu Patrick 
Published: August 2024

AbstractSummaryThe ever-growing genetic cohorts lead to an increase in scale of molecular Quantitative Trait Loci (QTL) studies, creating opportunities for more extensive two samples Mendelian randomization (MR) investigations aiming to identify causal relationships between molecular traits and diseases. This increase led to the identification of multiple causal candidates and potential drug targets over time. However, the increase in scale of such studies and higher dimension multi-omic data come with computational challenges. We present “LArge SCAle MOLecular Mendelian Randomization with Julia” (LaScaMolMR.jl), an open-sourced integrated Julia package optimized for Omic-wide Mendelian Randomization (OWMR) Studies. This versatile package eliminates the two-language problem and implements fast algorithms for instrumental variable selection approaches with both cis and trans instruments and performs the most popular regression estimators for MR studies with molecular exposures. It reduces the compute time via meta-programming allowing easy deployment of multi-threaded approach and the internalization of linkage disequilibrium investigation of potential instrumental variables. Via its integrated approach and high-computational performance, LaScaMolMR.jl allows users who have minimal programming experience to perform large scale OWMR studies.Implementation and availabilityLaScaMolMR is freely available atgithub.com/SamuelMathieu-code/LaScaMolMR.jl.
Structures of the cyanobacterial nitrogen regulators NtcA and PipX complexed to DNA fully clarify DNA binding by NtcA and recruitment of RNA polymerase by PipX
Authors: Forcada-Nadal Alicia , Bibak Sirine , Salinas Paloma , Contreras Asunción , Rubio Vicente , Llácer José L. 
Published: August 2024

AbstractThe CRP-FNR superfamily of transcriptional regulators includes the cyanobacterial master regulator NtcA, which orchestrates large responses of cyanobacteria to nitrogen scarcity. NtcA uses as allosteric activator 2-oxoglutarate (2OG), a signal of nitrogen poorness and carbon richness, and binds a coactivating protein (PipX) that shuttles between the signaling protein PII and NtcA depending on nitrogen richness, thus connecting PII signaling and gene expression regulation. Here, combining structural (X-ray crystallography of six types of crystals including NtcA complexes with DNA, 2OG and PipX), modelling and functional (EMSA and bacterial two-hybrid) studies, we clarify the reasons for the exquisite specificity for the binding of NtcA to its target DNA, its mechanisms of activation by 2OG, and its coactivation by PipX. Our crystal structures of PipX-NtcA-DNA complexes prove that PipX does not interact with DNA, although it increases NtcA-DNA contacts, and that it stabilizes the active, DNA-binding-competent conformation of NtcA. Superimposition of this complex on a very recently reported cryoEM structure of NtcA in a Transcription Activity Complex with RNA polymerase (RNAP), shows that PipX binding helps recruit RNAP by PipX interaction with RNAP, particularly with its gamma and sigma (region 4) subunits, a structural prediction supported here by bacterial two-hybrid experiments.
Co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species
Authors: Magesh Shruthi , Schrope Jonathan H. , Mercado Soto Nayanna , Li Chao , Hurley Amanda I. , Huttenlocher Anna , Beebe David J. , Handelsman Jo 
Published: August 2024

AbstractBiofilms are three-dimensional structures containing one or more bacterial species embedded in extracellular polymeric substances. Although most biofilms are stationary,Flavobacterium johnsoniaeforms a motile spherical biofilm called a zorb, which is propelled by its base cells and contains a polysaccharide core. Here, we report formation of spatially organized, motile, multispecies biofilms, designated “co-zorbs,” that are distinguished by a core-shell structure.F. johnsoniaeforms zorbs whose cells collect other bacterial species and transport them to the zorb core, forming a co-zorb. Live imaging revealed that co-zorbs also form in zebrafish, thereby demonstrating a new type of bacterial movement in vivo. This discovery opens new avenues for understanding community behaviors, the role of biofilms in bulk bacterial transport, and collective strategies for microbial success in various environments.Significance StatementThis paper reports the discovery of co-zorbs, which are spherical aggregates of bacteria that move and transport other bacteria. Zorbs move toward other bacteria and collect them in a manner reminiscent of phagocytes. Once inside the zorb, the new species form a striking, organized core. The discovery of co-zorbs introduces an entirely new type of bacterial movement and transport involving cooperation among bacterial species. Co-zorbs have potential for engineering microbial systems for biotechnology applications and for managing spread of bacterial pathogens in their hosts.
The C2 domain augments Ras GTPase Activating Protein catalytic activity
Authors: Paul Maxum E. , Chen Di , Vish Kimberly J. , Lartey Nathaniel L. , Hughes Elizabeth , Freeman Zachary T. , Saunders Thomas L. , Stiegler Amy L. , King Philip D. , Boggon Titus J. 
Published: August 2024

AbstractRegulation of Ras GTPases by GTPase activating proteins (GAP) is essential for their normal signaling. Nine of the ten GAPs for Ras contain a C2 domain immediately proximal to their canonical GAP domain, and in RasGAP (p120GAP, p120RasGAP;RASA1) mutation of this domain is associated with vascular malformations in humans. Here, we show that the C2 domain of RasGAP is required for full catalytic activity towards Ras. Analysis of the RasGAP C2-GAP crystal structure, AlphaFold models, and sequence conservation reveal direct C2 domain interaction with the Ras allosteric lobe. This is achieved by an evolutionarily conserved surface centered around RasGAP residue R707, point mutation of which impairs the catalytic advantage conferred by the C2 domainin vitro. In mice,R707Cmutation phenocopies the vascular and signaling defects resulting from constitutive disruption of theRASA1gene. In SynGAP, mutation of the equivalent conserved C2 domain surface impairs catalytic activity. Our results indicate that the C2 domain is required to achieve full catalytic activity of Ras GTPase activating proteins.
Invariant Natural Killer T cells control positively and negatively the development of hepatocellular carcinoma
Authors: Papanastasatou Maria , Gioulbasani Marianthi , Nakou Evangelia , Galaras Alexandros , Rubio-Tomás Teresa , Talianidis Iannis , Eliopoulos Aristides , Hatzis Pantelis , Verykokakis Mihalis 
Published: August 2024

AbstractThe liver routinely encounters antigens from the gut, triggering pro- inflammatory responses. Unresolved inflammation can lead to liver damage, steatosis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is influenced by various immune cells, including invariant natural killer T (iNKT) cells, which exhibit both innate and adaptive immunity traits. Here, we examined iNKT cell dynamics in a diethyl-nitrosamine (DEN)-induced HCC mouse model. We observed a significant reduction in iNKT cell numbers in HCC livers due to apoptosis and impaired cytokine production.CD1d-deficient mice, which lack iNKT cells, displayed delayed tumor initiation and lower tumor and foci number. However, these tumors were larger in size and characterized by enhanced proliferation and immunosuppression. Interestingly, adoptive transfer of healthy iNKT cells post-tumor establishment reduced tumor burden, highlighting their potential therapeutic role. Our findings suggest that iNKT cells contribute to early HCC development, while in later stages they help to control tumor growth, thus underscoring their complex role in liver carcinogenesis. Further understanding of iNKT cell functions may inform novel immunotherapeutic strategies for HCC management.
5’UTR translational inhibition of neuroblastoma dependency factors using the CR-1-31-B rocaglate
Authors: Nunes C , Bekaert SL , Parsa S , Nelen I , Martens F , De Stanchina E , Sanders E , Hilgert E , T’sas S , Zhao P , De Vloed F , Eggermont A , Goossens S , Sablina A , Depestel L , Wendel HG , Durinck K 
Published: August 2024

SummaryCurrent therapies for neuroblastoma are often ineffective and survivors suffer from severe long-term therapy related side-effects, underscoring the need for identification of novel drugging strategies. We performed an in-depth evaluation of phenotypic and molecular responses following exposure of neuroblastoma cells to the rocaglate CR-1-31-B, scrutinizing its mode-of-action through integrative ribosome footprinting and shotgun proteome profiling. We could show that CR-1-31-B significantly reduces tumor growthin vivowithout apparent toxicity. By means of combined ribosome footprinting and transcriptome analysis we uncovered that CR-1-31-B treatment downregulates translation efficiencies of several major neuroblastoma dependencies includingMYCN,CCND1andALKas well as factors involved in the G2/M checkpoint. Upregulated targets are enriched for oxidative phosphorylation pathway components and DNA repair. At the proteome level, CR-1-31-B imposed downregulation of a FOXM1 driven signature, including the FOXM1 target geneTPX2. We show that neuroblastoma cells are dependent on TPX2 for growth and DNA repair and further demonstrate enhanced CHK1 sensitivity upon TPX2 knockdown. Next, we also observed synergistic effects of CHK1 inhibition with CR-1-31-B. In conclusion, our data support CR-1-31-B as a potent novel therapeutic agent in neuroblastoma, in particular in combination with DNA damage or replication stress inducing agents.
Liprin-α/RIM complex regulates the dynamic assembly of presynaptic active zones via liquid-liquid phase separation
Authors: Jin Gaowei , Campos Joaquín , Liu Yang , de la Cruz Berta Marcó , Zhang Shujing , Liang Mingfu , Li Kaiyue , Xie Xingqiao , Yu Cong , Sterky Fredrik H. , Acuna Claudio , Wei Zhiyi 
Published: August 2024

AbstractPresynaptic scaffold proteins, including liprin-α, RIM, and ELKS, are pivotal to the assembly of the active zone and regulating the coupling of calcium signals and neurotransmitter release, yet the underlying mechanism remains poorly understood. Here, we determined the crystal structure of the liprin-α2/RIM1 complex, revealing a multifaceted intermolecular interaction that drives the liprin-α/RIM assembly. Neurodevelopmental disease-associated mutations block the formation of the complex. Disrupting this interaction in neurons impairs synaptic transmission and reduces the readily releasable pool of synaptic vesicles. Super-resolution imaging analysis supports a role for liprin-α in recruiting RIM1 to the active zone, presumably by promoting the liquid-liquid phase separation (LLPS) of RIM1. Strikingly, the liprin-α/RIM interaction modulates the competitive distribution of ELKS1 and voltage-gated calcium channels (VGCCs) in RIM1 condensates. Disrupting the liprin-α/RIM interaction significantly decreased VGCC accumulation in the condensed phase and rendered release more sensitive to the slow calcium buffer EGTA, suggesting an increased physical distance between VGCC and vesicular calcium sensors. Together, our findings provide a plausible mechanism of the liprin-α/RIM complex in regulating the coupling of calcium channels and primed synaptic vesicles via LLPS for efficient synaptic transmission and uncover the pathological implication of liprin-α mutations in neurodevelopmental disorders.
Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways
Authors: Askarova Aydan , Yaa Reuben M. , Marzi Sarah J. , Nott Alexi 
Published: August 2024

AbstractGenome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA) we identified disease risk genes for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.
NRH, a potent NAD+ booster, improves glucose homeostasis and lipid metabolism in diet-induced obese mice though an active adenosine kinase pathway
Authors: Zeng Xinliu , Wang Yongjie , Farias Karina , Rappa Andrew , Darko Chirstine , Sauve Anthony , Yang Yue 
Published: August 2024

AbstractNAD+deficiency underlies obesity-induced metabolic disturbances. Here we evaluated the treatment effect of a new and potent NAD+enhancer, dihydronicotinamide riboside (NRH), in diet-induced obese mice with hyperglycemia and hyperlipidemia. Administering NRH for 7 weeks improved glucose homeostasis by enhancing pancreatic beta-cell functional mass, increasing muscle insulin sensitivity, and reducing hepatic gluconeogenesis. NRH treatment also mobilized fat deposition, reduced circulating lipid, and improved white adipose function. Significant elevation in multi-tissue NAD+levels and sirtuin (SIRT) activities, especially SIRT3, mediated these metabolic improvements. Inhibiting adenosine kinase (ADK), a newly recognized enzyme in the NRH-induced NAD+synthesis pathway, blocked NRH’s effect in improving glucose and lipid metabolism. ADK inhibition also reduced tissue NAD+elevation and the subsequent activation of SIRT3, suggesting an active ADK pathway is necessary for NRH-induced metabolic benefits. These observations, for the first time, establish NRH as a promising intervention for correcting obesity-induced metabolic syndrome.
Transcription factors SlMYB41, SlMYB92 and SlWRKY71 regulate gene expression in the tomato exodermis
Authors: Jo Leonardo , Buti Sara , Artur Mariana A. S. , Kluck Rianne M.C. , Cantó-Pastor Alex , Brady Siobhán M. , Kajala Kaisa 
Published: August 2024

AbstractRoot barrier cell types, like the endodermis and exodermis, are crucial for plant acclimation to environmental stresses. Deposition of suberin, a hydrophobic polymer, in these cell layers restricts the movement of molecules and plays a vital role in stress responses. This study investigates the role of SlMYB41, SlMYB92 and SlWRKY71 transcription factors (TFs) in regulating suberin biosynthesis in the tomato (Solanum lycopersicum) root exodermis by genetic perturbation. Genetic perturbation of these TFs altered exodermal suberin deposition patterns, indicating the SlMYBs as positive and SlWRKY71 negative regulators of suberization. RNA sequencing revealed a significant overlap between differentially expressed genes regulated by these TFs, suggesting a shared regulatory network. Gene set enrichment analyses highlighted their role in lipid and suberin biosynthesis as well as overrepresentation of exodermis-enriched transcripts. Furthermore, transactivation assays demonstrated that these two MYBs promote the expression of suberin-related genes, while SlWRKY71 represses them. These results indicate a complex antagonistic relationship, advancing our understanding of the regulatory mechanisms controlling exodermis suberization in tomato roots.HighlightMYB and WRKY transcription factors collaboratively regulate suberin biosynthesis in the tomato root exodermis. Antagonistic interactions may fine-tune suberization or act as a break to stop overaccumulation.