bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer
Authors: He Zhiwei , Wang Jie , Xu Jian , Jiang Xueyi , Liu Xinyuan , Jiang Jianxin 
Published: October 2022

AbstractPancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion depolymerization. To identify the key motor protein involving in the integrin β1 recycling, we screened kinesin proteins involved in integrin β1 recycling using a kinesin family siRNA library and identified kinesin family 15 (KIF15) as a key regulator. KIF15 was upregulated in metastasis PC tissues and promoted PC cell migration and invasion. We identified KIF15 as a key component mediating integrin β1/FAK signaling that accelerated FA disassembly in a FAK-Y397-dependent manner. KIF15 recruited PI3K-C2α to promote integrin β1/FAK signaling and FA disassembly in a RAB11A-dependent manner. The C-terminal tail of KIF15 is required for the PI3K-C2α interaction and RAB11A activation. In addition, we also found that SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation, which is the key activation event in motor protein function. Together, these findings indicate that KIF15 interacts with PI3K-C2α to promote FA turnover in PC cells by controlling the endosome recycling of integrin β1 in a SIRT1 acetylation modification-dependent manner, eventually promoting focal adhesions turnover and distant metastasis in PC.
Role of ferroptosis on tumor progression and immunotherapy
Authors: Gong Deting , Chen Mingjun , Wang Yuhan , Shi Juanjuan , Hou Yongzhong 
Published: October 2022

AbstractFerroptosis is triggered by intracellular iron leading to accumulation of lipid peroxidation consequent promotion of cell death. Cancer cell exhibits ability to evade ferroptosis by activation of antioxidant signaling pathways such as SLC7A11/GPX4 axis. In addition to transcriptional regulation on ferroptosis by NRF2, SREBP1, YAP, and p53, ferroptosis is modulated by ubiquitination or autophagic degradation. Moreover, zinc or Ca2+ could modulate ferroptosis by inducing lipid peroxidation and ferroptosis. Induction of ferroptosis enhances immune cell activity such as T cells or macrophages, which is associated with the release of DAMPs (damage-associated molecular patterns) and IFNγ. Therefore, combined immune checkpoint inhibitors with ferroptosis inducers effectively enhance antitumor immunotherapy, whereas induction of ferroptosis could impair T cell activity or survival, suggesting that rational combined therapy for cancer is essential. In this review, we discussed the regulatory role of ferroptosis on tumor progression and immunotherapy.
An MSH6 germline pathogenic variant p.Gly162Ter associated with Lynch syndrome
Authors: Vostrukhina Olga A. , Mirlina Elena D. , Khmelkova Darya N. , Butrovich Galina M. , Shakhmatova Alexandra D. , Kil Yury V. , Polyatskin Yliya L. , Artemyeva Anna S. , Gulyaev Alexey V. , Verbenko Valery N. 
Published: October 2022

AbstractWe identified a three-generation Russian family with Lynch syndrome with a novel germline variant of the MSH6 gene. An 84-year-old female was diagnosed with endometrial adenocarcinoma at the age of 49 years. Her son was diagnosed with colorectal tubular adenoma at the age of 32 years. A germline nonsense variant (c.484 G > T:p.Gly162Ter) in exon 3 of the MSH6 gene was revealed by whole-exome sequencing. Sanger sequencing confirmed the cosegregation of the MSH6 nonsense variant in family members.
Salience memories formed by value, novelty and aversiveness jointly shape object responses in the prefrontal cortex and basal ganglia
Authors: Ghazizadeh Ali , Hikosaka Okihide 
Published: October 2022

AbstractEcological fitness depends on maintaining object histories to guide future interactions. Recent evidence shows that value memory changes passive visual responses to objects in ventrolateral prefrontal cortex (vlPFC) and substantia nigra reticulata (SNr). However, it is not known whether this effect is limited to reward history and if not how cross-domain representations are organized within the same or different neural populations in this corticobasal circuitry. To address this issue, visual responses of the same neurons across appetitive, aversive and novelty domains were recorded in vlPFC and SNr. Results showed that changes in visual responses across domains happened in the same rather than separate populations and were related to salience rather than valence of objects. Furthermore, while SNr preferentially encoded outcome related salience memory, vlPFC encoded salience memory across all domains in a correlated fashion, consistent with its role as an information hub to guide behavior.
Subcellular localization of type IV pili regulates bacterial multicellular development
Authors: Ellison Courtney K. , Fei Chenyi , Dalia Triana N. , Wingreen Ned S. , Dalia Ankur B. , Shaevitz Joshua W. , Gitai Zemer 
Published: October 2022

AbstractIn mammals, subcellular protein localization of factors like planar cell polarity proteins is a key driver of the multicellular organization of tissues. Bacteria also form organized multicellular communities, but these patterns are largely thought to emerge from regulation of whole-cell processes like growth, motility, cell shape, and differentiation. Here we show that a unique intracellular patterning of appendages known as type IV pili (T4P) can drive multicellular development of complex bacterial communities. Specifically, dynamic T4P appendages localize in a line along the long axis of the cell in the bacterium Acinetobacter baylyi. This long-axis localization is regulated by a functionally divergent chemosensory Pil-Chp system, and an atypical T4P protein homologue (FimV) bridges Pil-Chp signaling and T4P positioning. We further demonstrate through modeling and empirical approaches that subcellular T4P localization controls how individual cells interact with one another, independently of T4P dynamics, with different patterns of localization giving rise to distinct multicellular architectures. Our results reveal how subcellular patterning of single cells regulates the development of multicellular bacterial communities.
Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes
Authors: Yuan Xiaoxiao , Wang Ruirui , Han Bing , Sun ChengJun , Chen Ruimin , Wei Haiyan , Chen Linqi , Du Hongwei , Li Guimei , Yang Yu , Chen Xiaojuan , Cui Lanwei , Xu Zhenran , Fu Junfen , Wu Jin , Gu Wei , Chen Zhihong , Fang Xin , Yang Hongxiu , Su Zhe , Wu Jing , Li Qiuyue , Zhang Miaoying , Zhou Yufeng , Zhang Lei , Ji Guang , Luo Feihong 
Published: October 2022

AbstractGut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.
Common evolutionary origin of acoustic communication in choanate vertebrates
Authors: Jorgewich-Cohen Gabriel , Townsend Simon William , Padovese Linilson Rodrigues , Klein Nicole , Praschag Peter , Ferrara Camila R. , Ettmar Stephan , Menezes Sabrina , Varani Arthur Pinatti , Serano Jaren , Sánchez-Villagra Marcelo R. 
Published: October 2022

AbstractAcoustic communication, broadly distributed along the vertebrate phylogeny, plays a fundamental role in parental care, mate attraction and various other behaviours. Despite its importance, comparatively less is known about the evolutionary roots of acoustic communication. Phylogenetic comparative analyses can provide insights into the deep time evolutionary origin of acoustic communication, but they are often plagued by missing data from key species. Here we present evidence for 53 species of four major clades (turtles, tuatara, caecilian and lungfish) in the form of vocal recordings and contextual behavioural information accompanying sound production. This and a broad literature-based dataset evidence acoustic abilities in several groups previously considered non-vocal. Critically, phylogenetic analyses encompassing 1800 species of choanate vertebrates reconstructs acoustic communication as a homologous trait, and suggests that it is at least as old as the last common ancestor of all choanate vertebrates, that lived approx. 407 million years before present.
Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
Authors: Paul Debasish , Kales Stephen C. , Cornwell James A. , Afifi Marwa M. , Rai Ganesha , Zakharov Alexey , Simeonov Anton , Cappell Steven D. 
Published: October 2022

AbstractThe F-box protein beta-transducin repeat containing protein (β-TrCP) acts as a substrate adapter for the SCF E3 ubiquitin ligase complex, plays a crucial role in cell physiology, and is often deregulated in many types of cancers. Here, we develop a fluorescent biosensor to quantitatively measure β-TrCP activity in live, single cells in real-time. We find β-TrCP remains constitutively active throughout the cell cycle and functions to maintain discreet steady-state levels of its substrates. We find no correlation between expression levels of β-TrCP and β-TrCP activity, indicating post-transcriptional regulation. A high throughput screen of small-molecules using our reporter identifies receptor-tyrosine kinase signaling as a key axis for regulating β-TrCP activity by inhibiting binding between β-TrCP and the core SCF complex. Our study introduces a method to monitor β-TrCP activity in live cells and identifies a key signaling network that regulates β-TrCP activity throughout the cell cycle.
Eya-controlled affinity between cell lineages drives tissue self-organization during Drosophila oogenesis
Authors: Weichselberger Vanessa , Dondl Patrick , Classen Anne-Kathrin 
Published: October 2022

AbstractCooperative morphogenesis of cell lineages underlies the development of functional units and organs. To study mechanisms driving the coordination of lineages, we investigated soma-germline interactions during oogenesis. From invertebrates to vertebrates, oocytes develop as part of a germline cyst that consists of the oocyte itself and so-called nurse cells, which feed the oocyte and are eventually removed. The enveloping somatic cells specialize to facilitate either oocyte maturation or nurse cell removal, which makes it essential to establish the right match between germline and somatic cells. We uncover that the transcriptional regulator Eya, expressed in the somatic lineage, controls bilateral cell–cell affinity between germline and somatic cells in Drosophila oogenesis. Employing functional studies and mathematical modelling, we show that differential affinity and the resulting forces drive somatic cell redistribution over the germline surface and control oocyte growth to match oocyte and nurse cells with their respective somatic cells. Thus, our data demonstrate that differential affinity between cell lineages is sufficient to drive the complex assembly of inter-lineage functional units and underlies tissue self-organization during Drosophila oogenesis.
Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Authors: Martins Filipe Correia , Couturier Dominique-Laurent , de Santiago Ines , Sauer Carolin Margarethe , Vias Maria , Angelova Mihaela , Sanders Deborah , Piskorz Anna , Hall James , Hosking Karen , Amirthanayagam Anumithra , Cosulich Sabina , Carnevalli Larissa , Davies Barry , Watkins Thomas B. K. , Funingana Ionut G. , Bolton Helen , Haldar Krishnayan , Latimer John , Baldwin Peter , Crawford Robin , Eldridge Matthew , Basu Bristi , Jimenez-Linan Mercedes , Mcpherson Andrew W. , McGranahan Nicholas , Litchfield Kevin , Shah Sohrab P. , McNeish Iain , Caldas Carlos , Evan Gerard , Swanton Charles , Brenton James D. 
Published: October 2022

AbstractChromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.
Optogenetic-controlled immunotherapeutic designer cells for post-surgical cancer immunotherapy
Authors: Yu Yuanhuan , Wu Xin , Wang Meiyan , Liu Wenjing , Zhang Li , Zhang Ying , Hu Zhilin , Zhou Xuantong , Jiang Wenzheng , Zou Qiang , Cai Fengfeng , Ye Haifeng 
Published: October 2022

AbstractSurgical resection is the main treatment option for most solid tumors, yet cancer recurrence after surgical resection remains a significant challenge in cancer therapy. Recent advances in cancer immunotherapy are enabling radical cures for many tumor patients, but these technologies remain challenging to apply because of side effects related to uncontrollable immune system activation. Here, we develop far-red light-controlled immunomodulatory engineered cells (FLICs) that we load into a hydrogel scaffold, enabling the precise optogenetic control of cytokines release (IFN-β, TNF-α, and IL-12) upon illumination. Experiments with a B16F10 melanoma resection mouse model show that FLICs-loaded hydrogel implants placed at the surgical wound site achieve sustainable release of immunomodulatory cytokines, leading to prevention of tumor recurrence and increased animal survival. Moreover, the FLICs-loaded hydrogel implants elicit long-term immunological memory that prevents against tumor recurrence. Our findings illustrate that this optogenetic perioperative immunotherapy with FLICs-loaded hydrogel implants offers a safe treatment option for solid tumors based on activating host innate and adaptive immune systems to inhibit tumor recurrence after surgery. Beyond extending the optogenetics toolbox for immunotherapy, we envision that our optogenetic-controlled living cell factory platform could be deployed for other biomedical contexts requiring precision induction of bio-therapeutic dosage.
Revealing the role of ionic liquids in promoting fuel cell catalysts reactivity and durability
Authors: Avid Arezoo , Ochoa Jesus López , Huang Ying , Liu Yuanchao , Atanassov Plamen , Zenyuk Iryna V. 
Published: October 2022

AbstractIonic liquids (ILs) have shown to be promising additives to the catalyst layer to enhance oxygen reduction reaction in polymer electrolyte fuel cells. However, fundamental understanding of their role in complex catalyst layers in practically relevant membrane electrode assembly environment is needed for rational design of highly durable and active platinum-based catalysts. Here we explore three imidazolium-derived ionic liquids, selected for their high proton conductivity and oxygen solubility, and incorporate them into high surface area carbon black support. Further, we establish a correlation between the physical properties and electrochemical performance of the ionic liquid-modified catalysts by providing direct evidence of ionic liquids role in altering hydrophilic/hydrophobic interactions within the catalyst layer interface. The resulting catalyst with optimized interface design achieved a high mass activity of 347 A g−1Pt at 0.9 V under H2/O2, power density of 0.909 W cm−2 under H2/air and 1.5 bar, and had only 0.11 V potential decrease at 0.8 A cm−2 after 30 k accelerated stress test cycles. This performance stems from substantial enhancement in Pt utilization, which is buried inside the mesopores and is now accessible due to ILs addition.
Polerovirus N-terminal readthrough domain structures reveal molecular strategies for mitigating virus transmission by aphids
Authors: Schiltz Carl J. , Wilson Jennifer R. , Hosford Christopher J. , Adams Myfanwy C. , Preising Stephanie E. , DeBlasio Stacy L. , MacLeod Hannah J. , Van Eck Joyce , Heck Michelle L. , Chappie Joshua S. 
Published: October 2022

AbstractPoleroviruses, enamoviruses, and luteoviruses are icosahedral, positive sense RNA viruses that cause economically important diseases in food and fiber crops. They are transmitted by phloem-feeding aphids in a circulative manner that involves the movement across and within insect tissues. The N-terminal portion of the viral readthrough domain (NRTD) has been implicated as a key determinant of aphid transmission in each of these genera. Here, we report crystal structures of the NRTDs from the poleroviruses turnip yellow virus (TuYV) and potato leafroll virus (PLRV) at 1.53-Å and 2.22-Å resolution, respectively. These adopt a two-domain arrangement with a unique interdigitated topology and form highly conserved dimers that are stabilized by a C-terminal peptide that is critical for proper folding. We demonstrate that the PLRV NRTD can act as an inhibitor of virus transmission and identify NRTD mutant variants that are lethal to aphids. Sequence conservation argues that enamovirus and luteovirus NRTDs will follow the same structural blueprint, which affords a biological approach to block the spread of these agricultural pathogens in a generalizable manner.
Subcellular spatial transcriptomics identifies three mechanistically different classes of localizing RNAs
Authors: Cassella Lucia , Ephrussi Anne 
Published: October 2022

AbstractIntracellular RNA localization is a widespread and dynamic phenomenon that compartmentalizes gene expression and contributes to the functional polarization of cells. Thus far, mechanisms of RNA localization identified in Drosophila have been based on a few RNAs in different tissues, and a comprehensive mechanistic analysis of RNA localization in a single tissue is lacking. Here, by subcellular spatial transcriptomics we identify RNAs localized in the apical and basal domains of the columnar follicular epithelium (FE) and we analyze the mechanisms mediating their localization. Whereas the dynein/BicD/Egl machinery controls apical RNA localization, basally-targeted RNAs require kinesin-1 to overcome a default dynein-mediated transport. Moreover, a non-canonical, translation- and dynein-dependent mechanism mediates apical localization of a subgroup of dynein-activating adaptor-encoding RNAs (BicD, Bsg25D, hook). Altogether, our study identifies at least three mechanisms underlying RNA localization in the FE, and suggests a possible link between RNA localization and dynein/dynactin/adaptor complex formation in vivo.
Cone opponent functional domains in primary visual cortex combine signals for color appearance mechanisms
Authors: Li Peichao , Garg Anupam K. , Zhang Li A. , Rashid Mohammad S. , Callaway Edward M. 
Published: October 2022

AbstractStudies of color perception have led to mechanistic models of how cone-opponent signals from retinal ganglion cells are integrated to generate color appearance. But it is unknown how this hypothesized integration occurs in the brain. Here we show that cone-opponent signals transmitted from retina to primary visual cortex (V1) are integrated through highly organized circuits within V1 to implement the color opponent interactions required for color appearance. Combining intrinsic signal optical imaging (ISI) and 2-photon calcium imaging (2PCI) at single cell resolution, we demonstrate cone-opponent functional domains (COFDs) that combine L/M cone-opponent and S/L + M cone-opponent signals following the rules predicted from psychophysical studies of color perception. These give rise to an orderly organization of hue preferences of the neurons within the COFDs and the generation of hue “pinwheels”. Thus, spatially organized neural circuits mediate an orderly transition from cone-opponency to color appearance that begins in V1.
Deciphering the atomic-scale structural origin for large dynamic electromechanical response in lead-free Bi0.5Na0.5TiO3-based relaxor ferroelectrics
Authors: Yin Jie , Shi Xiaoming , Tao Hong , Tan Zhi , Lv Xiang , Ding Xiangdong , Sun Jun , Zhang Yang , Zhang Xingmin , Yao Kui , Zhu Jianguo , Huang Houbing , Wu Haijun , Zhang Shujun , Wu Jiagang 
Published: October 2022

AbstractDespite the extraordinary electromechanical properties of relaxor ferroelectrics, correlating their properties to underlying atomic-scale structures remains a decisive challenge for these “mess” systems. Here, taking the lead-free relaxor ferroelectric Bi0.5Na0.5TiO3-based system as an example, we decipher the atomic-scale structure and its relationship to the polar structure evolution and large dynamic electromechanical response, using the direct atomic-scale point-by-point correlation analysis. With judicious chemical modification, we demonstrate the increased defect concentration is the main driving force for deviating polarizations with high-angle walls, leading to the increased random field. Meanwhile, the main driving force for deviating polarizations with low-angle walls changes from the anti-phase oxygen octahedral tilting to the multidirectional A-O displacement, leading to the decreased anisotropy field. Benefiting from the competitive and synergetic equilibrium of anisotropic field versus random field, the facilitated polarization rotation and extension versus facilitated domain switching are identified to be responsible for the giant electromechanical response. These observations lay a foundation for understanding the “composition-structure-property” relationships in relaxor ferroelectric systems, guiding the design of functional materials for electromechanical applications.