bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligocene‐Miocene Exhumation of the Pinaleño Metamorphic Core Complex, Southeastern Arizona: Support for Magmatism and Plate Margin Reorganization as Controls on Regional Exhumation Trends
Authors: Chapman James B. , Scoggin Shane H. , Jepson Gilby , Ricketts Jason W. , Schaen Allen J. , Trzinski Adam E. 
Published: April 2024

AbstractThe Pinaleño Mountains of southeastern Arizona is the eastern‐most metamorphic core complex in the southern U.S. and northern Mexican Cordillera. This study investigates the thermal history and exhumation record of the Pinaleño core complex using mica 40Ar/39Ar, apatite and zircon (U‐Th)/He, and apatite fission‐track thermochronometers. The Pinaleño Mountains experienced two periods of rapid cooling during the Cenozoic. The first period, from ca. 27 to 21 Ma, records tectonic exhumation related to the development of the core complex and extensional shear zone. This period was followed by a relatively quiescent interval from 21 to 13.5 Ma that records little to no exhumation. The second period of rapid cooling, from 13.5 to 11 Ma, records tectonic exhumation related to high‐angle normal faulting, characteristic of the Basin and Range province. The exhumation timing of the Pinaleño core complex matches previously recognized spatiotemporal trends in the southern Basin and Range province and indicates that core complex exhumation in this region started in southeastern Arizona (ca. 32–33°N) and migrated both northward and southward. These trends correlate well with the latitude and timing of subduction of the Pacific‐Farallon spreading ridge and the migration of the Mendocino (northward) and Rivera (southward) triple junctions. Spatiotemporal core complex exhumation trends also correlate well with regional magmatism associated with the mid‐Cenozoic flare‐up, including syn‐extensional intrusive rocks found in the footwalls of core complexes.
Cortico-striatal differences in the epigenome in attention-deficit/ hyperactivity disorder
Authors: Shastri Gauri G. , Sudre Gustavo , Ahn Kwangmi , Jung Benjamin , Kolachana Bhaskar , Auluck Pavan K. , Elnitski Laura , Marenco Stefano , Shaw Philip 
Published: April 2024

AbstractWhile epigenetic modifications have been implicated in ADHD through studies of peripheral tissue, to date there has been no examination of the epigenome of the brain in the disorder. To address this gap, we mapped the methylome of the caudate nucleus and anterior cingulate cortex in post-mortem tissue from fifty-eight individuals with or without ADHD. While no single probe showed adjusted significance in differential methylation, several differentially methylated regions emerged. These regions implicated genes involved in developmental processes including neurogenesis and the differentiation of oligodendrocytes and glial cells. We demonstrate a significant association between differentially methylated genes in the caudate and genes implicated by GWAS not only in ADHD but also in autistic spectrum, obsessive compulsive and bipolar affective disorders through GWAS. Using transcriptomic data available on the same subjects, we found modest correlations between the methylation and expression of genes. In conclusion, this study of the cortico-striatal methylome points to gene and gene pathways involved in neurodevelopment, consistent with studies of common and rare genetic variation, as well as the post-mortem transcriptome in ADHD.
PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway
Authors: Ma Yuanzhen , Fang Zhiyu , Zhang Hongning , Qi Yijun , Mao Yuke , Zheng Junfang 
Published: April 2024

AbstractEpidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells.
USP12 facilitates gastric cancer progression via stabilizing YAP
Authors: Zhang Peng , Liu Dongyi , Zang Yifeng , Wang Jinqing , Liu Ziping , Zhu Jian , Li Xin , Ding Yinlu 
Published: April 2024

AbstractThe dysregulation of Hippo signaling is a crucial factor driving the progression of gastric cancer, making the targeting of the Hippo pathway a promising therapeutic strategy. However, effective drugs targeting the Hippo/YAP axis remain unavailable. Thus, identifying potential therapeutic targets and mechanisms that inhibit the activity of the Hippo/YAP axis in gastric cancer is of paramount importance. The ubiquitination modification of the Hippo/YAP pathway plays a significant role in signaling transduction and cancer progression. In an effort to shed light on effective therapeutic targets, we conducted a screening using a deubiquitinase small interfering RNA library, leading to the identification of USP12 as an important deubiquitinase in the context of Hippo/YAP axis and the progression of gastric cancer. Our bioinformatic analysis further demonstrated a correlation between USP12 and poor survival, as well as a positive association with classical YAP target genes in gastric cancer samples. Notably, USP12 depletion was found to inhibit gastric cancer progression via the Hippo/YAP axis, whereas USP12 overexpression exhibited the opposite effect, promoting gastric cancer growth and enhancing YAP activity. Further studies through immuno-staining and immuno-precipitation assays indicated the nuclear localization of USP12 and its association with YAP to enhance YAP stability. Specifically, our findings revealed that USP12 could inhibit K48-linked poly-ubiquitination of YAP, predominantly at the K315 site. As a result, we have identified a novel regulatory mechanism involving USP12 and Hippo signaling in the progression of gastric cancer, with the potential for blockade of USP12 to materialize as a promising strategy for combating gastric cancer.
Structural basis for human Cav3.2 inhibition by selective antagonists
Authors: Huang Jian , Fan Xiao , Jin Xueqin , Lyu Chen , Guo Qinmeng , Liu Tao , Chen Jiaofeng , Davakan Amaël , Lory Philippe , Yan Nieng 
Published: April 2024

AbstractThe Cav3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Cav3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.
Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy
Authors: Zhu Bo , Yin Hang , Zhang Di , Zhang Meiling , Chao Xiaojuan , Scimeca Luca , Wu Ming-Ru 
Published: April 2024

AbstractImmunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.
Beyond nothingness in the formation and functional relevance of voids in polymer films
Authors: Kalutantirige Falon C. , He Jinlong , Yao Lehan , Cotty Stephen , Zhou Shan , Smith John W. , Tajkhorshid Emad , Schroeder Charles M. , Moore Jeffrey S. , An Hyosung , Su Xiao , Li Ying , Chen Qian 
Published: April 2024

AbstractVoids—the nothingness—broadly exist within nanomaterials and impact properties ranging from catalysis to mechanical response. However, understanding nanovoids is challenging due to lack of imaging methods with the needed penetration depth and spatial resolution. Here, we integrate electron tomography, morphometry, graph theory and coarse-grained molecular dynamics simulation to study the formation of interconnected nanovoids in polymer films and their impacts on permeance and nanomechanical behaviour. Using polyamide membranes for molecular separation as a representative system, three-dimensional electron tomography at nanometre resolution reveals nanovoid formation from coalescence of oligomers, supported by coarse-grained molecular dynamics simulations. Void analysis provides otherwise inaccessible inputs for accurate fittings of methanol permeance for polyamide membranes. Three-dimensional structural graphs accounting for the tortuous nanovoids within, measure higher apparent moduli with polyamide membranes of higher graph rigidity. Our study elucidates the significance of nanovoids beyond the nothingness, impacting the synthesis‒morphology‒function relationships of complex nanomaterials.
Pathogenic mutations of human phosphorylation sites affect protein–protein interactions
Authors: Rrustemi Trendelina , Meyer Katrina , Roske Yvette , Uyar Bora , Akalin Altuna , Imami Koshi , Ishihama Yasushi , Daumke Oliver , Selbach Matthias 
Published: April 2024

AbstractDespite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) of proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% of pathogenic missense mutations are found in IDRs, and understanding how such mutations affect PPIs is essential for unraveling disease mechanisms. Here, we employ peptide-based interaction proteomics to investigate 36 disease-associated mutations affecting phosphorylation sites. Our results unveil significant differences in interactomes between phosphorylated and non-phosphorylated peptides, often due to disrupted phosphorylation-dependent SLiMs. We focused on a mutation of a serine phosphorylation site in the transcription factor GATAD1, which causes dilated cardiomyopathy. We find that this phosphorylation site mediates interaction with 14-3-3 family proteins. Follow-up experiments reveal the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal. Our results demonstrate that pathogenic mutations of human phosphorylation sites can significantly impact protein-protein interactions, offering insights into potential molecular mechanisms underlying pathogenesis.
Violation of emergent rotational symmetry in the hexagonal Kagome superconductor CsV3Sb5
Authors: Fukushima Kazumi , Obata Keito , Yamane Soichiro , Hu Yajian , Li Yongkai , Yao Yugui , Wang Zhiwei , Maeno Yoshiteru , Yonezawa Shingo 
Published: April 2024

AbstractSuperconductivity is caused by electron pairs that are canonically isotropic, whereas some exotic superconductors are known to exhibit non-trivial anisotropy stemming from unconventional pairings. However, superconductors with hexagonal symmetry, the highest rotational symmetry allowed in crystals, exceptionally have strong constraint that is called emergent rotational symmetry (ERS): anisotropic properties should be very weak especially near the critical temperature Tc even for unconventional pairings such as d-wave states. Here, we investigate superconducting anisotropy of the recently-found hexagonal Kagome superconductor CsV3Sb5, which is known to exhibit various intriguing phenomena originating from its undistorted Kagome lattice formed by vanadium atoms. Based on calorimetry performed under accurate two-axis field-direction control, we discover a combination of six- and two-fold anisotropies in the in-plane upper critical field. Both anisotropies, robust up to very close to Tc, are beyond predictions of standard theories. We infer that this clear ERS violation with nematicity is best explained by multi-component nematic superconducting order parameter in CsV3Sb5 intertwined with symmetry breakings caused by the underlying charge-density-wave order.
Amundsen Sea circulation controls bottom upwelling and Antarctic Pine Island and Thwaites ice shelf melting
Authors: Park Taewook , Nakayama Yoshihiro , Nam SungHyun 
Published: April 2024

AbstractThe Pine Island and Thwaites Ice Shelves (PIIS/TIS) in the Amundsen Sea are melting rapidly and impacting global sea levels. The thermocline depth (TD) variability, the interface between cold Winter Water and warm modified Circumpolar Deep Water (mCDW), at the PIIS/TIS front strongly correlates with basal melt rates, but the drivers of its interannual variability remain uncertain. Here, using an ocean model, we propose that the strength of the eastern Amundsen Sea on-shelf circulation primarily controls TD variability and consequent PIIS/TIS melt rates. The TD variability occurs because the on-shelf circulation meanders following the submarine glacial trough, creating vertical velocity through bottom Ekman dynamics. We suggest that a strong or weak ocean circulation, possibly linked to remote winds in the Bellingshausen Sea, generates corresponding changes in bottom Ekman convergence, which modulates mCDW upwelling and TD variability. We show that interannual variability of off-shelf zonal winds has a minor effect on ocean heat intrusion into PIIS/TIS cavities, contrary to the widely accepted concept.
Hydrophobic mismatch drives self-organization of designer proteins into synthetic membranes
Authors: Peruzzi Justin A. , Steinkühler Jan , Vu Timothy Q. , Gunnels Taylor F. , Hu Vivian T. , Lu Peilong , Baker David , Kamat Neha P. 
Published: April 2024

AbstractThe organization of membrane proteins between and within membrane-bound compartments is critical to cellular function. Yet we lack approaches to regulate this organization in a range of membrane-based materials, such as engineered cells, exosomes, and liposomes. Uncovering and leveraging biophysical drivers of membrane protein organization to design membrane systems could greatly enhance the functionality of these materials. Towards this goal, we use de novo protein design, molecular dynamic simulations, and cell-free systems to explore how membrane-protein hydrophobic mismatch could be used to tune protein cotranslational integration and organization in synthetic lipid membranes. We find that membranes must deform to accommodate membrane-protein hydrophobic mismatch, which reduces the expression and co-translational insertion of membrane proteins into synthetic membranes. We use this principle to sort proteins both between and within membranes, thereby achieving one-pot assembly of vesicles with distinct functions and controlled split-protein assembly, respectively. Our results shed light on protein organization in biological membranes and provide a framework to design self-organizing membrane-based materials with applications such as artificial cells, biosensors, and therapeutic nanoparticles.
Contrasting carbon cycle along tropical forest aridity gradients in West Africa and Amazonia
Authors: Zhang-Zheng Huanyuan , Adu-Bredu Stephen , Duah-Gyamfi Akwasi , Moore Sam , Addo-Danso Shalom D. , Amissah Lucy , Valentini Riccardo , Djagbletey Gloria , Anim-Adjei Kelvin , Quansah John , Sarpong Bernice , Owusu-Afriyie Kennedy , Gvozdevaite Agne , Tang Minxue , Ruiz-Jaen Maria C. , Ibrahim Forzia , Girardin Cécile A. J. , Rifai Sami , Dahlsjö Cecilia A. L. , Riutta Terhi , Deng Xiongjie , Sun Yuheng , Prentice Iain Colin , Oliveras Menor Imma , Malhi Yadvinder 
Published: April 2024

AbstractTropical forests cover large areas of equatorial Africa and play a substantial role in the global carbon cycle. However, there has been a lack of biometric measurements to understand the forests’ gross and net primary productivity (GPP, NPP) and their allocation. Here we present a detailed field assessment of the carbon budget of multiple forest sites in Africa, by monitoring 14 one-hectare plots along an aridity gradient in Ghana, West Africa. When compared with an equivalent aridity gradient in Amazonia, the studied West African forests generally had higher productivity and lower carbon use efficiency (CUE). The West African aridity gradient consistently shows the highest NPP, CUE, GPP, and autotrophic respiration at a medium-aridity site, Bobiri. Notably, NPP and GPP of the site are the highest yet reported anywhere for intact forests. Widely used data products substantially underestimate productivity when compared to biometric measurements in Amazonia and Africa. Our analysis suggests that the high productivity of the African forests is linked to their large GPP allocation to canopy and semi-deciduous characteristics.
Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Authors: Blanpain Lou T. , Cole Eric R. , Chen Emily , Park James K. , Walelign Michael Y. , Gross Robert E. , Cabaniss Brian T. , Willie Jon T. , Singer Annabelle C. 
Published: April 2024

AbstractModulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.
Evolution of T cells in the cancer-resistant naked mole-rat
Authors: Lin Tzuhua D. , Rubinstein Nimrod D. , Fong Nicole L. , Smith Megan , Craft Wendy , Martin-McNulty Baby , Perry Rebecca , Delaney Martha A. , Roy Margaret A. , Buffenstein Rochelle 
Published: April 2024

AbstractNaked mole-rats (NMRs) are best known for their extreme longevity and cancer resistance, suggesting that their immune system might have evolved to facilitate these phenotypes. Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of γδT cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic γδT-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 αβT cells exhibit modest clonotypic diversity. Consistently, perinatal NMR thymuses are considerably smaller than those of mice yet follow similar involution progression. Our findings suggest that NMRs have evolved under a relaxed intracellular pathogenic selective pressure that may have allowed cancer resistance and longevity to become stronger targets of selection to which the immune system has responded by utilizing γδT cells.
Plasmids in the human gut reveal neutral dispersal and recombination that is overpowered by inflammatory diseases
Authors: Zorea Alvah , Pellow David , Levin Liron , Pilosof Shai , Friedman Jonathan , Shamir Ron , Mizrahi Itzhak 
Published: April 2024

AbstractPlasmids are pivotal in driving bacterial evolution through horizontal gene transfer. Here, we investigated 3467 human gut microbiome samples across continents and disease states, analyzing 11,086 plasmids. Our analyses reveal that plasmid dispersal is predominantly stochastic, indicating neutral processes as the primary driver of their wide distribution. We find that only 20-25% of plasmid DNA is being selected in various disease states, constraining its distribution across hosts. Selective pressures shape specific plasmid segments with distinct ecological functions, influenced by plasmid mobilization lifestyle, antibiotic usage, and inflammatory gut diseases. Notably, these elements are more commonly shared within groups of individuals with similar health conditions, such as Inflammatory Bowel Disease (IBD), regardless of geographic location across continents. These segments contain essential genes such as iron transport mechanisms- a distinctive gut signature of IBD that impacts the severity of inflammation. Our findings shed light on mechanisms driving plasmid dispersal and selection in the human gut, highlighting their role as carriers of vital gene pools impacting bacterial hosts and ecosystem dynamics.