bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia
Authors: Di Biase Maria A. , Geaghan Michael P. , Reay William R. , Seidlitz Jakob , Weickert Cynthia Shannon , Pébay Alice , Green Melissa J. , Quidé Yann , Atkins Joshua R. , Coleman Michael J. , Bouix Sylvain , Knyazhanskaya Evdokiya E. , Lyall Amanda E. , Pasternak Ofer , Kubicki Marek , Rathi Yogesh , Visco Andrew , Gaunnac Megan , Lv Jinglei , Mesholam-Gately Raquelle I. , Lewandowski Kathryn E. , Holt Daphne J. , Keshavan Matcheri S. , Pantelis Christos , Öngür Dost , Breier Alan , Cairns Murray J. , Shenton Martha E. , Zalesky Andrew 
Published: February 2022

AbstractBrain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
Abnormal dynamic functional connectivity during fear extinction learning in PTSD and anxiety disorders
Authors: Wen Zhenfu , Seo Jeehye , Pace-Schott Edward F. , Milad Mohammed R. 
Published: February 2022

AbstractExamining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders.
Broad phylogenetic and functional diversity among mixotrophic consumers of Prochlorococcus
Authors: Li Qian , Edwards Kyle F , Schvarcz Christopher R , Steward Grieg F 
Published: February 2022

Abstract
Small eukaryotic phytoplankton are major contributors to global primary production and marine biogeochemical cycles. Many taxa are thought to be mixotrophic, but quantitative studies of phagotrophy exist for very few. In addition, little is known about consumers of Prochlorococcus, the abundant cyanobacterium at the base of oligotrophic ocean food webs. Here we describe thirty-nine new phytoplankton isolates from the North Pacific Subtropical Gyre (Station ALOHA), all flagellates ~2–5 µm diameter, and we quantify their ability to graze Prochlorococcus. The mixotrophs are from diverse classes (dictyochophytes, haptophytes, chrysophytes, bolidophytes, a dinoflagellate, and a chlorarachniophyte), many from previously uncultured clades. Grazing ability varied substantially, with specific clearance rate (volume cleared per body volume) varying over ten-fold across isolates and six-fold across genera. Slower grazers tended to create more biovolume per prey biovolume consumed. Using qPCR we found that the haptophyte Chrysochromulina was most abundant among the isolated mixotrophs at Station ALOHA, with 76–250 cells mL−1 across depths in the upper euphotic zone (5–100 m). Our results show that within a single ecosystem the phototrophs that ingest bacteria come from many branches of the eukaryotic tree, and are functionally diverse, indicating a broad range of strategies along the spectrum from phototrophy to phagotrophy.
Detection of circulating tumour cells before and following adjuvant chemotherapy and long-term prognosis of early breast cancer
Authors: Matikas Alexios , Kotsakis Athanasios , Apostolaki Stella , Politaki Helen , Perraki Maria , Kalbakis Kostas , Nikolaou Michalis , Economopoulou Panagiota , Hatzidaki Dora , Georgoulias Vassilis 
Published: February 2022

AbstractBackgroundThe detection of circulating tumour cells (CTC) is prognostic for disease recurrence in early breast cancer (BC). This study aims to investigate whether this prognostic effect persists or varies over time.MethodsThe study population consisted of prospectively included stage I–III BC patients. The presence ofCK19mRNA-positive CTC in the peripheral blood was evaluated before and after adjuvant chemotherapy, using a real-time RT–PCR assay. Longitudinal samples were collected for a subset of patients.ResultsBaseline CTC data were available from 1220 patients, while 1132 had both pre- and post-therapy data. After a median follow-up of 134.1 months, CTC positivity at baseline was associated with shorter overall survival (OS; HRadj = 1.72, 95% CI 1.34–2.21,p < 0.001). For disease-free survival, an interaction with time (p = 0.045) was observed. CTC positivity predicted early (within 5 years; HRadj = 1.76, 95%CI 1.33–2.32,p < 0.001) but not late recurrence (HRadj = 1.10, 95% CI 0.79–1.53,p = 0.577). Following adjuvant chemotherapy, more patients converted from CTC-positive to CTC-negative than vice versa (p < 0.001). Ten-year OS was 68.6% for + /+ and 86.7% for −/− group (p < 0.001). CTC status at follow-up predicted disease recurrence.ConclusionCTC detection pre- and post-adjuvant chemotherapy is prognostic for early relapse, supporting investigations for novel adjuvant therapeutic approaches.
Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation
Authors: Chen Rirong , Pang Xiaobai , Li Li , Zeng Zhirong , Chen Minhu , Zhang Shenghong 
Published: February 2022

AbstractThe exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn’s disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-β; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.
Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy
Authors: Ye Hui , Chen Chaobo , Wu Hanghang , Zheng Kang , Martín-Adrados Beatriz , Caparros Esther , Francés Rubén , Nelson Leonard J. , Gómez del Moral Manuel , Asensio Iris , Vaquero Javier , Bañares Rafael , Ávila Matías A. , Andrade Raúl J. , Isabel Lucena M. , Martínez-Chantar Maria Luz , Reeves Helen L. , Masson Steven , Blumberg Richard S. , Gracia-Sancho Jordi , Nevzorova Yulia A. , Martínez-Naves Eduardo , Cubero Francisco Javier 
Published: February 2022

AbstractAcetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1–2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.
Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice
Authors: Ni Libin , Xiao Jian , Zhang Di , Shao Zhenxuan , Huang Chongan , Wang Sheng , Wu Yaosen , Tian Naifeng , Sun Liaojun , Wu Aimin , Zhou Yifei , Wang Xiangyang , Zhang Xiaolei 
Published: February 2022

AbstractThe pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. Secondary injury is a major target for SCI therapy, whereas microglia play an important role in secondary injury. The immunoresponsive gene 1 (Irg-1) has been recorded as one of the most significantly upregulated genes in SCI tissues in gene chip data; however, its role in SCI remains unclear. This study aims to illustrate the role of Irg-1 as well as its regulated metabolite itaconate in SCI. It was demonstrated that the expression of Irg-1 was increased in spinal cord tissues in mice as well as in microglia stimulated by lipopolysaccharides (LPS). It was also shown that overexpression of Irg-1 may suppress LPS-induced inflammation in microglia, while these protective effects were attenuated by Nrf2 silencing. In vivo, overexpression of Irg-1 was shown to suppress neuroinflammation and improve motor function recovery. Furthermore, treatment of microglia with itaconate demonstrated similar inflammation suppressive effects as Irg-1 overexpression in vitro and improved motor function recovery in vivo. In conclusion, the current study shows that Irg-1 and itaconate are involved in the recovery process of SCI, either Irg-1 overexpression or itaconate treatment may provide a promising strategy for the treatment of SCI.
ADRB3 induces mobilization and inhibits differentiation of both breast cancer cells and myeloid-derived suppressor cells
Authors: Zhou Zhiling , Zhan Jiaxin , Luo Qiong , Hou Xinghua , Wang Shuxia , Xiao Dingzhang , Xie Zhi , Liang Haidan , Lin Shuguang , Zheng Meng 
Published: February 2022

AbstractMetastatic tumors are mainly composed of neoplastic cells escaping from the primary tumor and inflammatory cells egressing from bone marrow. Cancer cell and inflammatory cell are remained in the state of immaturity during migration to distant organs. Here, we show that ADRB3 is crucial in cell mobilization and differentiation. Immunohistochemistry revealed ADRB3 expression is significantly more frequent in breast cancer tissues than in adjacent noncancerous tissues (92.1% vs. 31.5%). Expression of ADRB3 correlated with malignant degree, TNM stage and poor prognosis. Moreover, ADRB3 expression was markedly high in activated disseminated tumor cells, myeloid-derived suppressor cells (MDSCs), lymphocytes and neutrophil extracellular traps of patients. Importantly, ADRB3 promoted the expansion of MDSC through stimulation of bone marrow mobilization and inhibiting of the differentiation of immature myeloid cells. Furthermore, ADRB3 promoted MCF-7 cells proliferation and inhibited transdifferentiation into adipocyte-like cell by activating mTOR pathway. Ultimately, the MDSC-deficient phenotype of ADRB3 -/- PyMT mice was associated with impairment of mammary tumorigenesis and reduction in pulmonary metastasis. Collectively, ADRB3 promotes metastasis by inducing mobilization and inhibiting differentiation of both breast cancer cells and MDSCs.
Overlooked and widespread pennate diatom-diazotroph symbioses in the sea
Authors: Schvarcz Christopher R. , Wilson Samuel T. , Caffin Mathieu , Stancheva Rosalina , Li Qian , Turk-Kubo Kendra A. , White Angelicque E. , Karl David M. , Zehr Jonathan P. , Steward Grieg F. 
Published: February 2022

AbstractPersistent nitrogen depletion in sunlit open ocean waters provides a favorable ecological niche for nitrogen-fixing (diazotrophic) cyanobacteria, some of which associate symbiotically with eukaryotic algae. All known marine examples of these symbioses have involved either centric diatom or haptophyte hosts. We report here the discovery and characterization of two distinct marine pennate diatom-diazotroph symbioses, which until now had only been observed in freshwater environments. Rhopalodiaceae diatomsEpithemia pelagicasp. nov. andEpithemia catenatasp. nov. were isolated repeatedly from the subtropical North Pacific Ocean, and analysis of sequence libraries reveals a global distribution. These symbioses likely escaped attention because the endosymbionts lack fluorescent photopigments, havenifHgene sequences similar to those of free-living unicellular cyanobacteria, and are lost in nitrogen-replete medium. Marine Rhopalodiaceae-diazotroph symbioses are a previously overlooked but widespread source of bioavailable nitrogen in marine habitats and provide new, easily cultured model organisms for the study of organelle evolution.
Structures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor
Authors: Bondarenko Vasyl , Wells Marta M. , Chen Qiang , Tillman Tommy S. , Singewald Kevin , Lawless Matthew J. , Caporoso Joel , Brandon Nicole , Coleman Jonathan A. , Saxena Sunil , Lindahl Erik , Xu Yan , Tang Pei 
Published: February 2022

AbstractThe intracellular domain (ICD) of Cys-loop receptors mediates diverse functions. To date, no structure of a full-length ICD is available due to challenges stemming from its dynamic nature. Here, combining nuclear magnetic resonance (NMR) and electron spin resonance experiments with Rosetta computations, we determine full-length ICD structures of the human α7 nicotinic acetylcholine receptor in a resting state. We show that ~57% of the ICD residues are in highly flexible regions, primarily in a large loop (loop L) with the most mobile segment spanning ~50 Å from the central channel axis. Loop L is anchored onto the MA helix and virtually forms two smaller loops, thereby increasing its stability. Previously known motifs for cytoplasmic binding, regulation, and signaling are found in both the helices and disordered flexible regions, supporting the essential role of the ICD conformational plasticity in orchestrating a broad range of biological processes.
Cotranslational N-degron masking by acetylation promotes proteome stability in plants
Authors: Linster Eric , Forero Ruiz Francy L. , Miklankova Pavlina , Ruppert Thomas , Mueller Johannes , Armbruster Laura , Gong Xiaodi , Serino Giovanna , Mann Matthias , Hell Rüdiger , Wirtz Markus 
Published: February 2022

AbstractN-terminal protein acetylation (NTA) is a prevalent protein modification essential for viability in animals and plants. The dominant executor of NTA is the ribosome tethered Nα-acetyltransferase A (NatA) complex. However, the impact of NatA on protein fate is still enigmatic. Here, we demonstrate that depletion of NatA activity leads to a 4-fold increase in global protein turnover via the ubiquitin-proteasome system in Arabidopsis. Surprisingly, a concomitant increase in translation, actioned via enhanced Target-of-Rapamycin activity, is also observed, implying that defective NTA triggers feedback mechanisms to maintain steady-state protein abundance. Quantitative analysis of the proteome, the translatome, and the ubiquitome reveals that NatA substrates account for the bulk of this enhanced turnover. A targeted analysis of NatA substrate stability uncovers that NTA absence triggers protein destabilization via a previously undescribed and widely conserved nonAc/N-degron in plants. Hence, the imprinting of the proteome with acetylation marks is essential for coordinating proteome stability.
Engineering and exploiting synthetic allostery of NanoLuc luciferase
Authors: Guo Zhong , Parakra Rinky D. , Xiong Ying , Johnston Wayne A. , Walden Patricia , Edwardraja Selvakumar , Moradi Shayli Varasteh , Ungerer Jacobus P. J. , Ai Hui-wang , Phillips Jonathan J. , Alexandrov Kirill 
Published: February 2022

AbstractAllostery enables proteins to interconvert different biochemical signals and form complex metabolic and signaling networks. We hypothesize that circular permutation of proteins increases the probability of functional coupling of new N- and C- termini with the protein’s active center through increased local structural disorder. To test this we construct a synthetically allosteric version of circular permutated NanoLuc luciferase that can be activated through ligand-induced intramolecular non-covalent cyclisation. This switch module is tolerant of the structure of binding domains and their ligands, and can be used to create biosensors of proteins and small molecules. The developed biosensors covers a range of emission wavelengths and displays sensitivity as low as 50pM and dynamic range as high as 16-fold and could quantify their cognate ligand in human fluids. We apply hydrogen exchange kinetic mass spectroscopy to analyze time resolved structural changes in the developed biosensors and observe ligand-mediated folding of newly created termini.
Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats
Authors: Kay Yuni , Tsan Linda , Davis Elizabeth A. , Tian Chen , Décarie-Spain Léa , Sadybekov Anastasiia , Pushkin Anna N. , Katritch Vsevolod , Kanoski Scott E. , Herring Bruce E. 
Published: February 2022

AbstractMutations in the putative glutamatergic synapse scaffolding protein SAP97 are associated with the development of schizophrenia in humans. However, the role of SAP97 in synaptic regulation is unclear. Here we show that SAP97 is expressed in the dendrites of granule neurons in the dentate gyrus but not in the dendrites of other hippocampal neurons. Schizophrenia-related perturbations of SAP97 did not affect CA1 pyramidal neuron synapse function. Conversely, these perturbations produce dramatic augmentation of glutamatergic neurotransmission in granule neurons that can be attributed to a release of perisynaptic GluA1-containing AMPA receptors into the postsynaptic densities of perforant pathway synapses. Furthermore, inhibiting SAP97 function in the dentate gyrus was sufficient to impair contextual episodic memory. Together, our results identify a cell-type-specific synaptic regulatory mechanism in the dentate gyrus that, when disrupted, impairs contextual information processing in rats.
Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Authors: Gunasekar Susheel K. , Xie Litao , Kumar Ashutosh , Hong Juan , Chheda Pratik R. , Kang Chen , Kern David M. , My-Ta Chau , Maurer Joshua , Heebink John , Gerber Eva E. , Grzesik Wojciech J. , Elliot-Hudson Macaulay , Zhang Yanhui , Key Phillip , Kulkarni Chaitanya A. , Beals Joseph W. , Smith Gordon I. , Samuel Isaac , Smith Jessica K. , Nau Peter , Imai Yumi , Sheldon Ryan D. , Taylor Eric B. , Lerner Daniel J. , Norris Andrew W. , Klein Samuel , Brohawn Stephen G. , Kerns Robert , Sah Rajan 
Published: February 2022

AbstractType 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.