bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of α6-containing GABAA receptors induces antinociception under physiological and pathological conditions
Authors: Rodríguez-Palma Erick J. , De la Luz-Cuellar Yarim E. , Islas-Espinoza Ana M. , Félix-Leyva Adalberto E. , Shiers Stephanie I. , García Guadalupe , Torres-López Jorge E. , Delgado-Lezama Rodolfo , Murbartián Janet , Price Theodore J. , Granados-Soto Vinicio 
Published: August 2022

Abstract
The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through the activation of GABAA receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α6-containing GABAA receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α6-containing GABAA receptor blockade or transient α6-containing GABAA receptor knockdown induces evoked hypersensitivity and spontaneous pain in naive female rats. The α6 subunit is expressed in IB4+ and CGRP+ primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia but not astrocytes. Nerve injury reduces α6 subunit protein expression in the central terminals of the primary afferent neurons and dorsal root ganglia, whereas intrathecal administration of positive allosteric modulators of the α6-containing GABAA receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α6 subunit reduces tactile allodynia and restores α6 subunit expression in neuropathic rats. Positive allosteric modulators of the α6-containing GABAA receptor induces a greater antiallodynic effect in female rats and mice compared with male rats and mice. Finally, α6 subunit is expressed in humans. This receptor is found in CGRP+ and P2X3+ primary afferent fibers but not astrocytes in the human spinal dorsal horn. Our results suggest that the spinal α6-containing GABAA receptor has a sex-specific antinociceptive role in neuropathic pain, suggesting that this receptor may represent an interesting target to develop a novel treatment for neuropathic pain.
Diffusion Tensor Imaging as a Tool to Evaluate the Cognitive Function of Patients With Vascular Dementia
Authors: Zhang Qiuchi , Yan Xiwu , Du Jun , Chen Zhaoyao , Chang Cheng 
Published: August 2022

Background:
Vascular dementia (VaD) is the most common type of dementia secondary to Alzheimer’s disease. The pathologic mechanism of VaD is complex, and VaD still lacks a more objective diagnosis and evaluation method. Diffusion tensor imaging (DTI) can better detect the organizational structure and functional characteristics compared with any other diagnosis methods. Therefore, DTI has broad application in evaluating the severity and prognosis of VaD. This study aimed to assess the value of DTI in evaluating the cognitive function of patients with VaD.

Methods:
Authors searched Pubmed, Embase, and Cochrane Library, using the search terms, such as “diffusion tensor imaging”, “DTI”, “Vascular Dementia”, “Arteriosclerotic Dementia”, “Cognition”, and “Cognitive”. A voxel-based meta-analysis combined with quality statistics was performed, using the anisotropic effect-size version of the signed differential mapping method.

Results:
A total of 8 case-control studies were included in this meta-analysis. The sample size of patients ranged from 35 to 60, including 166 patients in the VaD group and 177 healthy individuals. The DTI imaging of the brain tissue of VaD patients was significantly different from that of healthy individuals.

Conclusions:
DTI imaging of the brain tissue of VaD patients was clearly different from that of healthy controls. Therefore it may be feasible to use DTI imaging as a diagnostic method for VaD.
Prevalence and Clinico-Radiologic Spectrum of Intracranial Atherosclerotic Disease-Related Stroke
Authors: Zafar Azra , Albakr Aishah , Shahid Rizwana , Alkhamis Fahd , Alabdali Majed , Aljaafari Danah , Nazish Saima , Ishaque Noman , Soltan Nehad Mahmoud , Msmar Amir H. , Al-Suhibani Sari Saleh , Al-Jehani Hosam 
Published: August 2022

Background:
Intracranial atherosclerotic disease (ICAD) is an important etiologic subtype of acute ischemic stroke (AIS). However, little direct evidence is available regarding ICAD-related stroke in Saudi Arabia (SA). This study aimed to identify the prevalence and describe the clinico-radiological spectrum of ICAD-related AIS in a SA cohort.

Methods:
This was a hospital-based retrospective study enrolling patients with ICAD-related AIS between 2017 and 2020. The electronic charts were reviewed. The mechanisms of stroke were identified as artery-to-artery embolization (AAE), in situ thrombotic occlusion, hypoperfusion, or perforator branch occlusion. Pearson’s χ2 test was performed to calculate the P values to establish the statistical significance of factors that could correlate with the mechanisms of stroke and functional outcome.

Results:
ICAD was found in 133 of AIS comprising 26% of total. Data from all patients were reviewed. Left ICA (25%) was the most frequently affected vessel. Territorial pattern (63.9%) was the most common infarct pattern, and AAE (44.3%) was the most common underlying mechanism. Perforator branch occlusion was more prevalent in women than in men. Malignant and hemorrhagic transformation (P=0.00) were more prevalent in the AAE group. Left-sided vascular involvement was statistically associated with unfavorable outcomes than the right (P=0.019).

Conclusions:
The prevalence of ICAD in our cohort from Western Asia did not differ from that in Southern Asia. ICA involvement was observed more frequently than previously reported. Further research from SA is required to better understand ICAD-related strokes in this region.
Dynamic Phosphorylation Regulates Eukaryotic Translation Initiation Factor 4A Activity During the Cell Cycle
Authors: Sahoo Ansuman , Zollo Robert A. , Shen Shichen , Ashraf Marium , Nelson Samantha , Koudelka Gerald , Qu Jun , Barbi Joseph , Walker Sarah E. 
Published: August 2022

ABSTRACTThe eukaryotic translation initiation factor 4A (eIF4A) resolves mRNA structures to support protein synthesis, yet little is known about its regulation. Here we analyzed eIF4A phosphorylation during alternate stages of the cell cycle, and found three residues near the DEAD box motif (T73, T146, and S177) underwent substantial phosphorylation changes. Phosphomimetic mutations T73D and T146D led to G2/M phase arrest, and abolished eIF4A interaction with RNA, suggesting eIF4A activity is needed for completion of cell division. In addition to these repressive events, we found that S177, a site immediately adjacent to the DEAD-box, showed diametrically opposed phosphorylation, with only phosphorylated S177 present during G1/S arrest and dephosphorylated S177 peptides during G2/M arrest. Phosphomimetic S177D eIF4A increased polysome levels and enhanced normally reduced eIF4A-eIF4G-interaction during G2/M, while phosphodeficient S177A decreased polysome levels and reduced growth, suggesting phosphorylation of S177 enhances eIF4A-mediated translation during G1/S. Together these results suggest that dynamic phosphorylation of eIF4A S177 serves to stimulate translation during G1/S, while inhibitory phosphorylation of additional sites holds the potential to rapidly transition eIF4A to an inactive state and turn off translation. These results also suggest an important role for eIF4A in coupling translation to cell cycle stages.
Haplogenome assembly reveals interspecific structural variation in Eucalyptus hybrids
Authors: Lötter Anneri , Duong Tuan A. , Candotti Julia , Mizrachi Eshchar , Wegrzyn Jill L. , Myburg Alexander A. 
Published: August 2022

SummaryDe novo phased (haplo)genome assembly using long-read DNA sequencing data has improved the detection and characterization of structural variants (SVs) in plant and animal genomes. Able to span across haplotypes, long reads allow phased, haplogenome assembly in highly outbred organisms such as forest trees. Eucalyptus tree species and interspecific hybrids are the most widely planted hardwood trees with F1 hybrids of Eucalyptus grandis and E. urophylla forming the bulk of fast-growing pulpwood plantations in subtropical regions. The extent of structural variation and its effect on interspecific hybridization is unknown in these trees. As a first step towards elucidating the extent of structural variation between the genomes of E. grandis and E. urophylla, we sequenced and assembled the haplogenomes contained in an F1 hybrid of the two species. Using Nanopore sequencing and a trio-binning approach, we assembled the separate haplogenomes (567 Mb and 545 Mb) to 98.8% BUSCO completion. High-density SNP genetic linkage maps of both parents allowed scaffolding of 88% of the haplogenome contigs into 11 pseudo-chromosomes (scaffold N50 of 43.82 Mb and 42.45 Mb for the E. grandis and E. urophylla haplogenomes, respectively). We identify 48,729 SVs between the two haplogenomes providing the first detailed insight into genome structural rearrangement in these species. The two haplogenomes have similar gene content, 35,572 and 33,915 functionally annotated genes, of which 34% are contained in genome rearrangements. Knowledge of SV and haplotype diversity in the two species will form the basis for understanding the genetic basis of hybrid superiority in these trees.Significance statementWe have produced phased, haplogenome assemblies of an interspecific F1 hybrid using a trio-binning approach and performed the first genome-wide analysis of genome synteny between a subtropical Eucalyptus tree species, E. grandis, and a tropical eucalypt, E. urophylla. This revealed a large number of previously undescribed genome structural variants as a step towards understanding genome structural evolution in this iconic genus of fast-growing woody perennials.
mNGS Investigation of Single Ixodes pacificus Ticks Reveals Diverse Microbes, Viruses, and a Novel mRNA-like Endogenous Viral Elements
Authors: Martyn Calla , Hayes Beth M. , Lauko Domokos , Mithun Edward , Castañeda Gloria , Bosco-Lauth Angela , Kistler Amy , Pollard Katherine S. , Chou Seemay 
Published: August 2022

AbstractTicks are increasingly important vectors of human and agricultural diseases. While many studies have focused on tick-borne bacteria, far less is known about tick-associated viruses and their roles in public health or tick physiology. To address this, we investigated patterns of bacterial and viral communities across two field populations of western black-legged ticks (Ixodes pacificus). Through metatranscriptomic analysis of 100 individual ticks, we quantified taxon prevalence, abundance, and co-occurrence with other members of the tick microbiome. Our analysis revealed 11 novel RNA viruses from Rhabdoviridae, Chuviridae, Picornaviridae, Phenuiviridae, Reoviridae, Solemovidiae, Narnaviridae, and 2 highly divergent RNA viruses lacking sequence similarity to known viral families. The majority of these viruses were also detectable in lab-raised ticks at all developmental life stages, localize to tick salivary glands, and show evidence of circulation in mice fed on by ticks. These data suggest that viruses are stable, heritable, and transmissible members of the tick microbiota. We also unexpectedly identified numerous virus-like transcripts that are associated with tick genomic DNA, most of which are distinct from known endogenous viral element-mediated immunity pathways in invertebrates. Together, our work reveals that in addition to potentially serving as vectors for potential viral pathogens, I. pacificus ticks may also have symbiotic partnerships with their own vertically-transmitted viruses or with ancient viruses through evolutionarily acquired virus-like transcripts. Our findings highlight how pervasive and intimate tick–virus interactions are, with major implications for both the fundamental physiology and vector biology of I. pacificus ticks.
Cryo-EM structure of the RADAR supramolecular anti-phage defense complex
Authors: Duncan-Lowey Brianna , Tal Nitzan , Johnson Alex G. , Rawson Shaun , Mayer Megan L. , Doron Shany , Millman Adi , Melamed Sarah , Fedorenko Taya , Kacen Assaf , Amitai Gil , Sorek Rotem , Kranzusch Philip J. 
Published: August 2022

SummaryRADAR is a two-protein bacterial defense system which was reported to defend against phage by ‘editing’ messenger RNA. Here we determine cryo-EM structures of the RADAR defense complex, revealing RdrA as a heptameric, two-layered AAA+ ATPase and RdrB as a dodecameric, hollow complex with twelve surface-exposed deaminase active sites. RdrA and RdrB join to form a giant assembly up to 10 MDa, with RdrA docked as a funnel over the RdrB active site. Surprisingly, our structures reveal a RdrB active site that targets mononucleotides, not RNA. We show that RdrB catalyzes ATP-to-ITP conversion in vitro and induces the accumulation of inosine mononucleotides during phage infection in vivo, limiting phage replication. Our results define ATP mononucleotide deamination as a determinant of RADAR immunity and reveal supramolecular assembly of a nucleotide-modifying machine as a novel mechanism of anti-phage defense.
Perpendicular Shear Stresses Drive Transmural Helical Remodeling in Engineered Human Ventricular Models
Authors: Williams Nisa P. , Beussman Kevin M. , Foster John R. , Rhodehamel Marcus , Williams Charles A. , Tsui Jonathan H. , Smith Alec S.T. , Mack David L. , Murry Charles E. , Sniadecki Nathan J. , Kim Deok-Ho 
Published: August 2022

AbstractTissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture.
MDC1 counteracts restrained replication fork restart and its loss causes chemoresistance in BRCA1/2-deficient mammary tumors
Authors: Liptay Martin , Barbosa Joana S. , Gogola Ewa , Duarte Alexandra A. , Dibitetto Diego , Schmid Jonas A. , Klebic Ismar , Mutlu Merve , Siffert Myriam , Francica Paola , Salguero Israel , van de Ven Marieke , Korte-Grimmerink Renske de , Jackson Stephen P. , Jonkers Jos , Lopes Massimo , Rottenberg Sven 
Published: August 2022

SUMMARYMDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly(ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2;p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology. MDC1 localizes at active replication forks during normal fork replication and its loss reduces fork speed. We show that MDC1 contributes to the restart of replication forks and thereby promotes sensitivity to PARPi and cisplatin. Loss of MDC1 causes MRE11-mediated resection, resulting in delayed fork restart. This improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. Hence, our results show a role for MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment
Authors: Chiorazzi Michael , Martinek Jan , Krasnick Bradley , Zheng Yunjiang , Robbins Keenan J , Qu Rihao , Kaufmann Gabriel , Skidmore Zachary , Henze Laura A , Brösecke Frederic , Adonyi Adam , Zhao Jun , Shan Liang , Sefik Esen , Mudd Jacqueline , Bi Ye , Goedegebuure S Peter , Griffith Malachi , Griffith Obi , Oyedeji Abimbola , Fertuzinhos Sofia , Garcia-Milian Rolando , Boffa Daniel , Detterbeck Frank , Dhanasopon Andrew , Blasberg Justin , Judson Benjamin , Gettinger Scott , Politi Katerina , Kluger Yuval , Palucka A Karolina , Fields Ryan , Flavell Richard A 
Published: August 2022

AbstractInteractions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by inter-species differences between human and mouse, as well as inter-person germline and somatic variation. Here we develop an autologous system that models the TME in individual patients. With patient-derived bone marrow, we engrafted a patient’s hematopoietic system in MISTRG6 mice followed by patient-derived xenograft (PDX) tissue, providing a genetically matched autologous model. We used this system to prospectively study tumor-immune interactions in solid tumor patients. Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent VEGF-A signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth, demonstrating the utility of the autologous PDX system for pre-clinical testing.
Group AStreptococcusantibiotic tolerance in necrotizing fasciitis
Authors: Keller Nadia , Boumasmoud Mathilde , Andreoni Federica , Tarnutzer Andrea , von Matt Manuela , Scheier Thomas C. , Gómez-Mejia Alejandro , Huemer Markus , Marques-Maggio Ewerton , Schuepbach Reto A. , Mairpady-Shambat Srikanth , Brugger Silvio D. , Zinkernagel Annelies S. 
Published: August 2022

AbstractObjectivesGroup AStreptococcus(GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, so-called persisters, are associated with difficult-to-treat infections, such as GAS-NF. In the present study, we investigated the presence of persistent GAS in tissue freshly debrided from three NF patients and examined more in depth the persisters phenomenon in GAS-NF clinical isolates.MethodsTime-lapse imaging of freshly isolated GAS-NF clinical isolates, the image analysis software ColTapp and antibiotic challenge-based persisters assays were used to assess the presence of persisters.ResultsWe show for the first time that GAS recovered directly from freshly debrided NF patient’s tissue are characterized by increased colony appearance time heterogeneity, indicating the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, similarly leads to phenotypic heterogeneity resulting in enhanced antibiotic survival and confirming the presence of GAS persisters.ConclusionsGAS persisters are present in the tissue freshly debrided from GAS-NF patients and might be one explanation for antibiotic treatment failure and surgery requirement in GAS-NF. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to increase GAS-NF therapy success.
A continuous epistasis model for predicting growth rate given combinatorial variation in gene expression and environment
Authors: Otto Ryan M. , Turska-Nowak Agata , Brown Philip M. , Reynolds Kimberly A. 
Published: August 2022

SummaryThe ability to predict changes in cellular growth rate given variation in gene expression is critical to engineer biosynthetic pathways and understand evolutionary constraints on mRNA abundance. However, the relationship between gene expression and growth rate is nonlinear and shaped by environmental and genetic context. To address these challenges, we examined the relationship between enzyme expression andE. coligrowth rate for 36 metabolic gene pairs by measuring growth following 4,404 pairwise, titrated changes in enzyme abundance under varied environmental contexts. Using 20% of these data, we trained an interpretable epistatic model to predict growth rate following simultaneous expression and environmental perturbations. The model’s predictions were robust to significant genetic and environmental epistasis and at times approached the accuracy of biological replicates. Based on these results, we propose a strategy using sparsely sampled, low-order measurements to quantify genetic interaction landscapes on the pathway-wide or genomic scale in a single assay.
Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC
Authors: Zheng Yanyan , Liu Dekang , Guo Hao , Chen Wenwen , Liu Zhaoyu , Li Zhaosu , Hu Tao , Zhang Yuanyuan , Li Xiang , Zhao Ziheng , Cai Qinglong , Ge Feifei , Fan Yu , Guan Xiaowei 
Published: August 2022

ABSTRACTPaternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH, insufficient to induce CPP normally, were used in F1 (METHF1). Selective antagonist (betaxolol) for β1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired METHF1-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without METHF1, but strongly evoked after METHF1treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without METHF1, which was kept at higher levels after METHF1treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed METHF1-evoked mPFC acyivation, and ultimately blocked METHF1-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKIImediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.HIGHLIGHTSPaternal methamphetamine (METH) exposure induces higher sensitivity to METH in male F1 during adulthood, accompanied with higher ADRB1 level in mPFC.METH use in F1 (METHF1) evokes more CaMKII-positive neurons in mPFC of METH-sired than saline-sired male F1.Inhibiting ADRB1 function or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) efficiently suppresses METHF1-evoked mPFC activation, and ultimately rescues transgenerational susceptibility to addiction in male F1.