bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted
Authors: Garcia Keith C. , Khan Ali A. , Ghosh Krishnendu , Sinha Souradip , Scalora Nicholas , DeWane Gillian , Fullenkamp Colleen , Merritt Nicole , Drebot Yuliia , Yu Samuel , Leidinger Mariah , Henry Michael D. , Breheny Patrick , Chimenti Michael S. , Tanas Munir R. 
Published: January 2025

Abstract/SummaryPurposeSarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically.Experimental designA tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines andin vivo.ResultsPI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effectin vivo, reducing tumor proliferation and size.ConclusionsTAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.
CHD2 Dosage Ties Autolysosomal Pathway to Cortical Maturation in Disease and Evolution
Authors: Leonardi Oliviero , Lewerissa Elly , Aprile Davide , Barakat Tahsin Stefan , Culotta Lorenza , Deng Ruizhi , Haazen Linda , Linda Katrin , Majoie Marian , Mordelt Annika , Ortale Aurelio , Oudakker Astrid , Prazzoli Filippo , Puvogel Sofia , Scheefhals Nicky , Schelhaas Helenius J , Schoenmaker Chantal , van Hugte Eline , van Bokhoven Hans , Verhoeven Judith , Vitriolo Alessandro , Boeckx Cedric , Testa Giuseppe , Kasri Nael Nadif 
Published: January 2025

AbstractThe relatively slow pace of cortical development in humans has long been a topic of investigation. Studies seeking to understand the underlying mechanisms have mostly focused on neurogenetic comparisons with extant species. Here we ask if developmental tempo differences may have also existed between us and our extinct relatives for whom genomes are available. To do so, we nominate asapiens-specific derived allele, virtually fixed in contemporary populations, which resides in an enhancer region active during early cortical development. The single nucleotide variant is predicted to significantly affect CHD2 expression, a chromatin remodeler known to play an important role in neural development and for which haploinsufficiency is associated with epilepsy and autism. We leverage patient induced pluripotent stem lines (iPSC) and engineered iPSCs in which we reintroduced the ancestral allele and generated heterozygous loss-of-function mutations. We reveal that CHD2 deficiency impairs lysosomal acidification and autophagosome flux. In contrast, ancestralized lines, which we find express higher levels of CHD2, exhibit enhanced lysosomal function and consequently accelerated autophagosome flux, consistent with our observations in chimpanzee and bonobo lines. This set of findings demonstrates that CHD2 dosage critically regulates the autolysosomal pathway. Through deep phenotyping of cortical organoid and neuron cultures, we show that the CHD2-modulated autolysosomal pathway impacts the timing of developmental programs, acquisition of neuronal functional properties and circuit maturation. Finally, we validate an estrogen-dependent rewiring of CHD2 regulation in the evolution of our lineage, providing a mechanistic understanding of how a single nucleotide variant in a regulatory region contributed to the modern pace of neuronal development and maturation. Together, our findings establish CHD2 as a regulator in setting neurodevelopmental tempo via the autolysosomal pathway.
Spatial Frequency Maps in Human Visual Cortex: A Replication and Extension
Authors: Ha Jiyeong , Broderick William F. , Kay Kendrick , Winawer Jonathan 
Published: January 2025

AbstractIn a step toward developing a model of human primary visual cortex, a recent study introduced a model of spatial frequency tuning in V1 (Broderick, Simoncelli, & Winawer, 2022). The model is compact, using just 9 parameters to predict BOLD response amplitude for locations across all of V1 as a function of stimulus orientation and spatial frequency. Here we replicated this analysis in a new dataset, the ‘nsdsynthetic’ supplement to the Natural Scenes Dataset (Allen et al., 2022), to assess generalization of model parameters. Furthermore, we extended the analyses to extrastriate maps V2 and V3. For each retinotopic map in the 8 NSD subjects, we fit the 9-parameter model. Despite many experimental differences between NSD and the original study, including stimulus size, experimental design, and MR field strength, there was good agreement in most model parameters. The dependence of preferred spatial frequency on eccentricity in V1 was similar between NSD and Broderick et al. Moreover, the effect of absolute stimulus orientation on spatial frequency maps was similar: higher preferred spatial frequency for horizontal and cardinal orientations compared to vertical and oblique orientations in both studies. The extension to extrastriate maps revealed that the biggest change in tuning between maps was in bandwidth: the bandwidth in spatial frequency tuning increased by 70% from V1 to V2 and 100% from V1 to V3, paralleling known increases in receptive field size. Together, the results show robust reproducibility and bring us closer to a systematic characterization of spatial encoding in the human visual system.
Distinct Genetic Populations and Resistance Backgrounds of the Malaria VectorAnopheles funestusin Tanzania
Authors: Odero Joel O. , Nambunga Ismail H. , Bwanary Hamis , Mkandawile Gustav , Paliga John M. , Mapua Salum A. , Mwinyi Sophia H. , Ngowo Halfan S. , Govella Nicodem J. , Kaindoa Emmanuel W. , Tripet Frédéric , Hernandez-Koutoucheva Anastasia , Ferguson Heather M. , Clarkson Chris S. , Miles Alistair , Weetman David , Baldini Francesco , Okumu Fredros O. , Dennis Tristan P. W. 
Published: January 2025

AbstractPopulation genetic analysis of mosquitoes is becoming increasingly important for understanding the distribution of insecticide resistance alleles, devising sustainable insecticide-based vector control approaches, and how malaria vector populations are structured in space.Anopheles funestusis the dominant malaria vector in Tanzania and most parts of East and Southern Africa. To better understand its population genomic structure in Tanzania, we sequenced the genomes of 334 individualAn. funestusmosquitoes from 11 administrative regions. We found two genetically differentiated populations; one inland and at high altitude (found in Katavi, Kagera, Kigoma, and Mwanza) and a second coastal, at low altitude (found in Pwani, Morogoro, Tanga, Ruvuma, Mtwara, Dodoma, and Lindi), with differences in genetic diversity and inbreeding. We found asynchronous selective sweeps, associated with insecticide resistance phenotypes, at theCyp9k1gene, andCyp6pgene cluster, with distinct copy number-variant profiles between the coastal and inland populations. These results suggest that inland and coastalAn. funestuspopulations have divergent histories, with the arid, central region of Tanzania, which also contains the Rift Valley being a possible barrier to gene flow. Such population disconnectedness should be considered for insecticide deployment, resistance management, and the rollout of novel genetic- based vector control approaches. These findings provide the most detailed study of TanzanianAn. funestuspopulation structure and resistance genetics to date. Future research should examine the epidemiological relevance of this discontinuity in gene flow and whether these populations have different malaria transmission abilities.
Defining epithelial stem cell heterogeneity through undulating structures of the skin and oral mucosa
Authors: Ishikawa Mizuho , Ngo Yen Xuan , Nishikawa Ikuto , Kato Hiroko , Maeda Ryo , Mizuno Ryosuke , Mizuno Jun , Izumi Kenji , Yanagisawa Hiromi , Sada Aiko 
Published: January 2025

SummaryEpithelial stem cells exhibit heterogeneity, with distinct stem cell populations occupying specific tissue regions. The human skin displays a characteristic undulating structure at the epidermal-dermal junction, which supports mechanical strength and influences the spatial organization of epithelial stem cells. Unlike human skin, mouse skin lacks these undulations, complicating studies into the effects of tissue architecture on stem cell distribution. Here, we leverage the mouse oral mucosa, which possesses an undulating structure similar to human skin, to characterize stem cell division dynamics and long-term fatein vivo. Using a combination of H2B-GFP pulse-chase analysis and lineage tracing with Dlx1-CreER and Slc1a3-CreER models, we demonstrate that slow-and fast-cycling stem cells localize to distinct anatomical regions relative to the undulating structure and maintain their respective compartments during tissue homeostasis. A three-dimensional culture model using micropatterned collagen scaffolds that recapitulate the undulating structuresin vitroreveals that the mechanical environment generated by the undulating structures partially induces proliferative heterogeneity in epithelial stem cells. This study proposes tissue undulating surface structure as a common principle as a niche component that defines the localization of compartmentalized stem cell populations across different epithelial tissues.Abstract Figure
A robust platform streamlining aromatic noncanonical amino acid biosynthesis and genetic code expansion inEscherichia coli
Authors: Zhang Jingxuan , Yu Keying , Xu Yali , Zhao Wushuang , Li Yulian , Wang Ying , Seebeck Florian P. , Chen Xiaohua , Liao Cangsong 
Published: January 2025

AbstractGenetic code expansion has significantly enhanced the diversity and functionality of proteins in the biological world, leading to a wide range of applications in catalysis, biology, and medicine. Despite the extraordinary advances in genetic code expansion over the past years, the availability and cost of noncanonical amino acids (ncAAs) remain one of the major obstacles, particularly for large-scale industrial production.In situbiosynthesis of ncAAs from commercially available precursors offers a promising solution to this challenge, yet only a few biosynthetic pathways for specific amino acids have been reported to date. To address this gap, we present a robust platform that couples the biosynthesis of aromatic amino acids with genetic code expansion inE. coli, enabling the production of proteins and peptides containing incorporated ncAAs. Forty amino acids with diverse functional groups were synthesized from aryl aldehydes by a biosynthetic pathway comprising two heterologously expressed enzymes and one endogenous enzyme. Nineteen of these amino acids were successfully incorporated into superfolder GFP (sfGFP) using three classic orthogonal translation systems. The platform’s versatility was further demonstrated by the production of macrocyclic peptides and antibodies containing functional ncAAs, such aspara-azidophenylalanine andpara-boronophenylalanine. We envision that the simplicity, efficiency, compatibility, and broad applicability of this biosynthetic pathway and the platform will greatly facilitate the production of peptides, enzymes, and antibodies containing ncAAs, thereby accelerating their use in various applications.Graphical abstract
Follicular mural granulosa cells stockpile glycogen to fuel corpus luteum pre-vascularization
Authors: Liao Jianning , Liu Qinghua , Liu Cong , Liu Guiqiong , Li Xiang , Wang Xiaodong , Wang Yaqin , Liu Ruiyan , Wu Hao , Shi Hongru , Zhao Yongheng , Ke Wenkai , Ran Zaohong , Wu Zian , Tan Bowen , Wang Chaoli , Jiang Xunping , Wang Quanfeng , Xie Qingzhen , Liu Guoshi , He Changjiu 
Published: January 2025

ABSTRACTThe differentiation of follicular mural granulosa cells (fGCs) into luteal cells involves a rapid progesterone synthesis surge and the vascular network development. However, progesterone elevation occurs before vascularization, leaving luteinizing fGCs temporarily devoid of blood supply. The mechanism of how fGCs fuel increased progesterone synthesis during this avascular phase remains unclear. Our research, utilizing integrative single-cell/spatial transcriptomics analysis and in vivo/ex vivo experiments, revealed that upon receiving the ovulatory/luteinization signal, fGCs transition to a low-energy state, reducing metabolic activity and storing glucose as glycogen. This process is governed by the LH (hCG)-Ras/Raf/Mek/Erk-RUNX1-Insulin signaling cascade. By mobilizing glycogen storage pre-vascularization, fGCs are fueled for enhanced progesterone synthesis. Supplementing glucose enhanced glycogen storage, leading to heightened progesterone secretion in corpora lutea. Implementing this technique, we enhanced luteal function in mice, sheep, and humans, resulting in increased litter rate in mice and improved pregnancy rates in sheep. Our study introduces the innovative concept of “fGC energy storage” and establishes the “Luteal Function Enhancement Technique”, contributing to the theoretical basis of reproductive physiology and displaying substantial clinical implications.
Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats
Authors: Hinds Nicole M. , Wojtas Ireneusz D. , Pulley Desta M. , McDonald Stephany J. , Spencer Colton D. , Sudarikov Milena , Hubbard Nicole E. , Kulick-Soper Colin M. , de Guzman Samantha , Hayden Sara , Debski Jessica J. , Patel Bianca , Fox Douglas P. , Manvich Daniel F. 
Published: January 2025

ABSTRACTPsychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brain’s hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock stress (n=12, 6/sex), or a no-stress control condition (n=12, 6/sex) immediately after the session’s conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking, perhaps in a sex-dependent manner.
Endothelial Slit2 guides the Robo1-positive sympathetic innervation during heart development
Authors: Zhao Juanjuan , Bruche Susann , Lekkos Konstantinos , Carr Carolyn , Vieira Joaquim M. , Parnavelas John G. , Andrews William D. , Mommersteeg Mathilda T.M. 
Published: January 2025

AbstractAxon guidance cues direct nerves in the heart during development, disease and regeneration. These cues determine cardiac innervation patterning by regulating the balance between chemo-attraction and chemo-repulsion. However, the role of one of the most crucial ligand-receptor combinations among axon guidance molecules, the Slit chemo-active ligands and their Roundabout (Robo) transmembrane receptors, remains unknown during cardiac innervation patterning. To test if Slit-Robo signalling is important for cardiac innervation guidance, we analysed Slit and Robo mouse knock-outs. ConstitutiveSlit2-/-ventricles showed significantly reduced innervation, whileSlit3-/-hearts showed temporary increased levels of innervation compared to wild-type littermate controls. Whereas innervation was not affected inRobo2-/-mice, the phenotype seen inSlit2-/-ventricles was recapitulated inRobo1-/-mice. Detailed expression analysis identified expression of Slit2 ligand in the endothelium of the coronary vessels, while Slit3 was highly present in the coronary smooth muscle wall and in the innervation. Both the Robo1 and Robo2 receptors were present in the nerves and at low levels in the vessels. Knocking outSlit2specifically in the endothelium recapitulated the defects seen in the constitutiveSlit2-/-hearts.Ex vivoaxon guidance cultures showed that attraction of axons extending from the ganglia was strongly reduced in ventricles with absence of endothelial Slit2 compared to wild-type controls. In absence of endothelial Slit2, adult mice showed reduced response to challenging the sympathetic innervation. In conclusion, we have identified an important new chemo-active Slit2-Robo1 pathway required for correct cardiac innervation development.
The Binary Cellular Biology of Human Growth: I. Quantifying the Creation and Growth of the Body and its Parts
Authors: Chodrow Philip , Su Jessica , Lee Daniel , He Neil , De Man Ruben , Tiwari Ankur , Mannherz William , Citi Luca , Gupta Rashi , Gu Zifan , Cantonwine David E , McElrath Thomas F , Tiemeier Henning , Michaelson James Selib 
Published: January 2025

ABSTRACTAssessing and understanding theGrowthandDevelopmentof animals generally, and of human fetuses specifically, provides essential information for the management of the health of the newborn and its mother. Here we show that a consideration of the formation of the body, in units of numbers of cells,N, and the change in these numbers by the binary either/or decisions of cells to divide or not, an approach we callBinary Cellular Analysis, provides new insights and new equations for quantifying the growth and development of the body and its parts. These equations include: 1) TheBinary Cellular Universal Growth Equation, which captures growth from conception to adulthood, and provides a method for biologically-based, data-driven,Growth Curves; 2) TheBinary Cellular Universal Mitotic Fraction Equation, which lies within theBinary Cellular Universal Growth Equation, and captures the mechanism of growth to adult size, control of cell division; 3) TheBinary Cellular Allometric Growth Equation, which captures the creation and growth of theTissues, Organs, andAnatomical Structuresof the body, and how the embryo creates eachBody Partfrom aSingle Founder Cell; and, 4)Binary Cellular Estimated Fetal Weight Equations, derived from theBinary Cellular Allometric Growth Equation, which captures the relationship betweenUltrasound Measurementand theSizeof the body as a whole. These equations capture the developmental process ofCellular Selection, resulting fromDifferential Cellular Proliferation, which molds the formation of the body from a single fertilized ovum into a multicellular animal. The parameters of these equations both capture the differences inSizeandGrowthbetween animals across the taxonomic spectrum, and between human fetuses, as well as identify the individual mechanisms of mitosis that driveGrowthandDevelopment. From theBinary Cellular Universal Growth Equation, theGrowthof human fetuses can be measured, thus providing a much-needed tool for understanding the biological forces that cause a fetus to grow toSmall, Average, orLarge Sizeat birth, for providing the basis of biologically-based, data-driven,Growth Curves, and for assisting the management of the obstetric care of the fetus and its mother.
Tau mediated regulation of Rho1- cytoskeletal dynamics in shaping renal tubule development inDrosophila
Authors: Tiwari Neha , Tapadia Madhu G. 
Published: January 2025

AbstractThe present study explored the significance of the microtubule-associated protein Tau in the morphogenesis and physiological processes of Malpighian tubules (MTs) inDrosophila melanogaster. Employing genetic manipulation techniques and microscopy, we established that Tau plays a crucial role in MTs development and function. Genetic ablation and RNAi-mediated suppression of Tau led to pronounced structural abnormalities, including cystic formations, non-uniform tubule diameters, and disorganized epithelial architecture. These aberrations are accompanied by perturbations in the cytoskeletal arrangement, compromised cellular polarity, and ionic imbalances. Functional analyses revealed deficiencies in salt homeostasis and fluid secretion within Tau-deficient tubules. Attenuation of Rho1 expression mitigated the structural defects observed in Tau mutants, highlighting the importance of Tau in modulating Rho1-mediated actin-microtubule dynamics suggesting a genetic interplay between Tau and Rho1 GTPase in orchestrating tubule morphogenesis The phenotypic parallels between Tau-deficient MTs and mammalian models of polycystic kidney disease implies an evolutionarily conserved function of Tau in tubular organ biology.Graphical Abstract
Automatic detection of fluorescently labeled synapses in volumetric in vivo imaging data
Authors: Chen Zhining , Coste Gabrielle I. , Li Evan , Huganir Richard L. , Graves Austin R. , Charles Adam S. 
Published: January 2025

SUMMARYSynapses are submicron structures that connect and enable communication between neurons. Many forms of learning are thought to be encoded by synaptic plasticity, wherein the strength of specific synapses is regulated by modulating expression of neurotransmitter receptors. For instance, regulation of AMPA-type glutamate receptors is a central mechanism controlling the formation and recollection of long-term memories. A critical step in understanding how synaptic plasticity drives behavior is thus to directly observe, i.e., image, fluorescently labeled synapses in living tissue. However, due to their small size and incredible density — with one ∼0.5 µm diameter synapse every cubic micron — accurately detecting individual synapses and segmenting each from its closely abutting neighbors is challenging. To overcome this, we trained a convolutional neural network to simultaneously detect and separate densely labeled synapses. These tools significantly increased the accuracy and scale of synapse detection, enabling segmentation of hundreds of thousands of individual synapses imaged in living mice.