bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transgene by Germplasm Interactions Can Impact Transgene Evaluation
Authors: Linares Julien F , Coles Nathan D , Mo Hua , Habben Jeff E , Humbert Sabrina , Messina Carlos , Tang Tom , Cooper Mark , Gho Carla , Carrasco Ricardo , Carter Javier , Flounders Jillian Wicher , Brummer E Charles 
Published: October 2022

ABSTRACTTransgenes have been successfully commercialized for qualitatively inherited insect and herbicide resistance traits that show similar effects across genetic backgrounds. However, for quantitative traits like yield, genetic background may affect the measured transgene value. In this paper, we evaluated whether different genetic backgrounds impact the estimated value of a transgene for grain yield, ear height, and anthesis-silking interval for maize by developing isogenic pairs of lines with and without a transgene and testing them in hybrid combination with non-transgenic lines from a complementary heterotic group across eleven environments in the USA. Over all hybrid combinations, the transgene increased yield by 0.2 Mg ha−1. Across multiple non-transgenic lines of the opposing heterotic group, the transgene effect within a line pair ranged from an increase of 0.8 Mg ha−1for the NSS4 and SS7 transgenic lines to a reduction of 0.3 Mg ha−1for the NSS5 transgenic line when compared to their non-transgenic isoline. Transgenic hybrids were often taller than non-transgenic hybrids (P<0.05). Anthesis to silking interval was reduced by 4□C growing degree units overall, but no transgene × genotype interaction was detected among line pairs. Our results show the importance of testing transgene efficacy across a large sample of elite hybrid pairs to assess the gene’s value. By only testing in a specific hybrid background, as may be done for qualitative traits like insect resistance, transgenes could be erroneously advanced or eliminated.
Targeting the pathological network: feasibility of network-based optimization of transcranial magnetic stimulation coil placement for treatment of psychiatric disorders
Authors: Cao Zhengcao , Xiao Xiang , Zhao Yang , Jiang Yihan , Xie Cong , Paillère-Martinot Marie-Laure , Artiges Eric , Li Zheng , Daskalakis Zafiris J. , Yang Yihong , Zhu Chaozhe 
Published: October 2022

AbstractIt has been recognized that the efficacy of TMS-based modulation may depend on the network profile of the stimulated regions throughout the brain. However, what profile of this stimulation network optimally benefits treatment outcomes is yet to be addressed. The answer to the question is crucial for informing network-based optimization of stimulation parameters, such as coil placement, in TMS treatments. In this study, we aimed to investigate the feasibility of taking a disease-specific network as the target of stimulation network for guiding individualized coil placement in TMS treatments. We present here a novel network-based model for TMS targeting of the pathological network. First, combining E-field modeling and resting-state functional connectivity, stimulation networks were modeled from locations and orientations of the TMS coil. Second, the spatial anti-correlation between the stimulation network and the pathological network of a given disease was hypothesized to predict the treatment outcome. The proposed model was validated to predict treatment efficacy from the position and orientation of TMS coils in two depression cohorts and one auditory verbal hallucinations cohort. We further demonstrate the utility of the proposed model in guiding individualized TMS treatment for psychiatric disorders. In this proof-of-concept study, we demonstrated the feasibility of the novel network-based targeting strategy that uses the whole-brain, system-level abnormity of a specific psychiatric disease as a target. Results based on empirical data suggest that the strategy may potentially be utilized to identify individualized coil parameters for maximal therapeutic effects.HighlightsProposed a model of targeting pathological brain networks for pre-treatment TMS coil placement planning in the treatment of psychiatric disorders;Validated the network targeting model in three cohorts of patients with depression or auditory verbal hallucinations, via prediction of individual TMS treatment efficacy from the parameters of coil placement;Demonstrated the utility of the network targeting model in guiding individualized TMS coil placement.
miR-148a-3pinhibits osteogenesis by targetingItga11via PI3K/Akt/GSK3/β-catenin pathway
Authors: Chen Xiaojun , Rong Kewei , Li Xin , Han Wenqing , Pang Yichuan , Chai Gang 
Published: October 2022

AbstractIn previous research, miR-148a-3p deficiency was observed in bone malformation in hemifacial microsomia. Nevertheless, the mechanism of miR-148a regulating osteogenesis remains unclear. Herein, in this article, we probed into the role of miR-148a-3p in bone physiology by utilizing miR-148a knock-out (KO) mice. Compared with wild-type (WT) or heterozygotic (HE) littermates, miR-148a knock-out mice manifested lower body weight, bone dysplasia with increased bone mass. Throughin-vitroexperiments, in terms of miR-148a-3p overexpression (miRNA mimic transfection) and knockout (primary cells from WT and KO littermates), we found that miR-148a-3p can suppress osteogenesis, either in the ALP activity or bone nodules formation. Afterward, by means of proteomics, combined with RNA-sequencing and prediction databases of microRNA targets (miRDB and TargetScan), nine candidate genes targeted by miR-148a-3p were identified. Among them, onlyItga11was regulated by mRNA degradation, while the others were modulated via post-transcriptional inhibition. Based on several online databases (GenePaint, BioGPS, STRING),Integrin Subunit Alpha 11(Itga11) was suggested to play an essential role in osteogenesis and it was confirmed as one direct target of miR-148a-3p by dual-luciferase reporter assay. Meanwhile, gene set enrichment analysis (GSEA) indicated activation of PI3K-Akt signaling pathway and WNT signaling pathway in miR-148a KO mice. The thereafter western blot confirmed that PI3K/Akt/GSK3/β-catenin signaling pathway was involved. Finally, with the help of esterase-response bone-affiliative liposome with theItga11siRNA delivery system, the enhanced osteogenesis in miR-148a KO mice was partly rescued. Taken together, we demonstrated that miR-148a-3p can inhibit osteogenesis by targeting Itga11 via PI3K/Akt/GSK3/β-catenin pathway.
From Initial Formation to Developmental Refinement: GABAergic Inputs Shape Neuronal Subnetworks in the Primary Somatosensory Cortex
Authors: Huang Jui-Yen , Hess Michael , Bajpai Abhinav , Li Xuan , Hobson Liam N , Xu Ashley J , Barton Scott J , Lu Hui-Chen 
Published: October 2022

SummaryNeuronal subnetworks, also known as ensembles, are functional units formed by interconnected neurons for information processing and encoding in the adult brain. Our study investigates the establishment of neuronal subnetworks in the mouse primary somatosensory (S1) cortex from postnatal days (P)11 to P21 usingin vivotwo-photon calcium imaging. We found that at P11, neuronal activity was highly synchronized but became sparser by P21. Clustering analyses revealed that while the number of subnetworks remained constant, their activity patterns became more distinct, with increased coherence, independent of cortical layer or sex. Furthermore, the coherence of neuronal activity within individual subnetworks significantly increased when synchrony frequencies were reduced by augmenting GABAergic activity at P15/16, a period when the neuronal subnetworks were still maturing. Together, these findings indicate the early formation of subnetworks and underscore the pivotal roles of GABAergic inputs in modulating S1 neuronal subnetworks.
C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation inMycobacterium smegmatis
Authors: Bag Kingshuk , Pal Aditya Kumar , Basu Subhadip , Singla Mamta , Chatterji Dipankar , Maiti Prabal Kumar , Ghosh Anirban , Jayaraman Narayanaswamy 
Published: October 2022

ABSTRACTHyperphosphorylated guanosine nucleotide (p)ppGpp, synthesized by Rel proteins, regulates the stringent response pathway responsible for biofilm growth and persister cell formation in the stationary phase of mycobacteria. The discovery of vitamin C as a potent inhibitor of Rel protein activities raises the prospect of such a tetrone lactone to prevent biofilm growth and persister cell formation. The closely related isotetrone lactone derivatives are identified in the present study as potent inhibitors of the above processes in a mycobacterium. Isotetrone lactone derivatives are synthesized from appropriate α-ketocarboxylic acids, derived from the a-amino acids. Aldol condensation with formaldehyde, followed by the lactone formation, completes synthesis of isotetrone derivatives, possessing varied substituents atC-4 carbon, in good yields. A series of biochemical evaluations of biofilm growth and persister cell formation inM. smegmatisis conducted. Among the derivatives, isotetrone possessing phenyl substituent atC-4 carbon completely inhibit the biofilm formation at 400 μg mL-1concentration, 84 h of post-exposure, followed by a moderate inhibition by the isotetrone possessingp-hydroxyphenyl substituent. Whereas, the latter isotetrone inhibits the growth of cells at 400 μg mL-1f.c. when monitored for 2 weeks, under PBS starvation condition. Isotetrones also potentiate the inhibition of antibiotic tolerant regrowth of cells by ciprofloxacin antibiotic (0.75 μg mL-1) and thus act as bio-enhancers. The combination is shown to significantly arrest the emergence of ciprofloxacin-resistant genetic mutants. The observations suggest that isotetrones in combination with ciprofloxacin are therapeutically superior when administered together. Systematic molecular dynamics studies show that isotetrone derivative binds to Rel protein more efficiently than vitamin C and the binding is aided by hydrogen bonding, van der Waals and electrostatic interactions at a binding site possessing serine, threonine, lysine and arginine residues. The present study establishes that the identified isotetrone derivatives (i) act as inhibitors ofM. smegmatisbiofilm growth and (ii) arrest the re-emergence of recalcitrant persister cells when administered together with ciprofloxacin antibiotic. Results of this study establish that isotetrones as new chemical entities that interfere with stringent response pathways in a mycobacterium under stress and permit overcoming the multidrug-resistant persister cell emergence in the bacterium.
STIM1 signals through NFAT independently of Orai1 and SOCE to regulate breast cancer cell migration
Authors: Hammad Ayat S. , Yu Fang , Horgen F. David , Machaca Khaled 
Published: October 2022

ABSTRACTStore-operated calcium entry (SOCE) contributes to several physiological and pathological conditions including transcription, secretion, immunodeficiencies, and cancer. SOCE has been shown to be important for breast cancer cell migration where knockdown of SOCE components (STIM1 or Orai1) decreases cancer metastasis. Here we show unexpectedly that STIM1 knockout (KO) metastatic MDA-MB-231 breast cancer cells migrate faster and have enhance invasion capacity compared to parental cells. In contrast, Orai1-KO cells, which have similar levels of SOCE inhibition as STIM1-KO, migrate slower than the parental cell line. This shows that the enhanced migration phenotype of STIM1-KO cells is not due to the loss of a Ca2+entry through SOCE, rather it involves transcriptional remodeling. Interestingly, NFATC2 is significantly downregulated in STIM1-KO cells and overexpression of NFATC2 reversed the enhanced migration of STIM1-KO cells. This demonstrates that STIM1 modulates NFATC2 expression independently of its role in SOCE.SUMMARY STATEMENTBreast cancer cells migrate faster when the ER Ca2+sensor STIM1 in knocked out due to downregulation of NFAT1 expression independent of Ca2+influx.
A genome-wide association study identified new variants associated with mathematical abilities in Chinese children
Authors: Zhang Liming , Wang Zhengjun , Zhu Zijian , Yang Qing , Cheng Chen , Zhao Shunan , Liu Chunyu , Zhao Jingjing 
Published: October 2022

AbstractMathematical ability is moderately heritable, and it is a complex trait which can be evaluated in several different categories. A few genetic studies have been published on general mathematical ability. However, no genetic study focused on specific mathematical ability categories. In this study, we separately performed genome-wide association studies (GWASs) on 11 mathematical ability categories in 1 146 students from Chinese elementary schools. We identified 7 genome-wide significant single nucleotide polymorphisms (SNPs) with strong linkage disequilibrium (LD) among each other (all r2>0.8) associated with mathematical reasoning ability (top SNP: rs34034296,p=2.01×10−8, nearest gene: CUB and Sushi multiple domains 3, CSMD3). We replicated one SNP (rs133885) from 585 SNPs previously reported to be associated with general mathematical ability associated with division ability in our data (p=1.053×10−5). In the gene- and gene-set enrichment analysis by MAGMA, we found three significant enrichments of associations with three mathematical ability categories for three genes. We also observed four significant enrichments of associations with four mathematical ability categories for three gene sets. Our results suggest new candidate genetic loci for the genetics of mathematical ability.
Universal chimeric Fcγ receptor T cells with appropriate affinity for IgG1 antibody exhibit optimal antitumor efficacy
Authors: Zhu Wen , Wang Yang , Lv Liangyin , Wang Hui , Shi Wenqiang , Liu Zexin , Zhou Mingzhe , Zhu Jianwei , Lu Huili 
Published: October 2022

AbstractDeveloping universal CARs with improved flexible targeting and controllable activities is urgently needed. While several studies have suggested the potential of CD16a in tandem with monoclonal antibodies to construct universal CAR T cells, the weak affinity between them is one of the limiting factors for efficacy. Herein, we systematically investigated the impact of Fcγ receptor (FcγR) affinity on CAR T cells properties by constructing universal CARs using Fcγ receptors with different affinities for IgG1 antibodies, namely CD16a, CD32a, and CD64. We demonstrated that the activities of these universal CAR T cells on tumor cells could be redirected and regulated by IgG1 antibodies. In xenografted mice, 64CAR chimeric Jurkat cells with the highest affinity showed significant antitumor effects in combination with herceptin in the Her2 low expression U251 MG model. However, in the CD20 high expression Raji model, 64CAR caused excessive activation of CAR-T cells, which resulted in cytokine release syndrome (CRS) and the decline of antitumor activity, and 32CAR with a moderate affinity brought the best efficacy. Our work extended the knowledge about FcγR-based universal CAR T cells and suggested that only the FcγRCAR with an appropriate affinity can offer the optimal antitumor advantages of CAR T cells.Graphical abstractUniversal CAR T cells based on Fcγ receptors exhibit a specific tumor-killing effect. However, the affinities of Fcγ receptors greatly influence the efficacy and adverse effectsin vivo.
Synaptopodin regulates denervation-induced plasticity at hippocampal mossy fiber synapses
Authors: Kruse Pia , Brandes Gudrun , Hemeling Hanna , Huang Zhong , Wrede Christoph , Hegermann Jan , Vlachos Andreas , Lenz Maximilian 
Published: October 2022

ABSTRACTNeurological diseases can lead to the denervation of brain regions caused by demyelination, traumatic injury or cell death. Nevertheless, the molecular and structural mechanisms underlying lesion-induced reorganization of denervated brain regions are a matter of ongoing investigation. In order to address this issue, we performed an entorhinal cortex lesion (ECL) in mouse organotypic entorhino-hippocampal tissue cultures of both sexes and studied denervation-induced plasticity of mossy fiber synapses, which connect dentate granule cells (dGCs) with CA3 pyramidal cells (CA3-PCs) and play important roles in spatial learning. Partial denervation caused a strengthening of excitatory neurotransmission in dGCs, in CA3-PCs, and their direct synaptic connections as revealed by paired recordings (GC-to-CA3). These functional changes were accompanied by ultrastructural reorganization of mossy fiber synapses, which regularly contain the plasticity-related protein synaptopodin and the spine apparatus organelle. We demonstrate that the spine apparatus organelle and its integral protein synaptopodin are associated with ribosomes in close proximity to synaptic sites and unravel a synaptopodin-related transcriptome. Notably, synaptopodin-deficient tissue preparations that lack the spine apparatus organelle, failed to express lesion-induced synaptic adjustments. Hence, synaptopodin and the spine apparatus organelle play a crucial role in regulating lesion-induced synaptic plasticity at hippocampal mossy fiber synapses.
Time or distance: predictive coding of Hippocampal cells
Authors: Abramson Shai , Kraus Benjamin J. , White John A. , Hasselmo Michael E. , Morris Genela , Derdikman Dori 
Published: October 2022

AbstractThe discovery of place cells within the hippocampus has pointed to the importance of the hippocampus for navigation. The more recent discovery of hippocampal time cells has broadened the perspective of encoding in the hippocampus. An alternative hypothesis to the existence of time cells is based on the notion that hippocampal cells deduce location by integrating travelled distance (“path integration”). According to this alternate hypothesis, time cells, which fire at particular times when animals are running on a treadmill without changing location, actually encode accumulated distance on the treadmill. To examine this hypothesis, Kraus et al.1performed treadmill experiments in which animals either ran for a fixed time or a fixed distance with varying velocities. Two distinct coding modes of hippocampal principal cells were found. Some cells encoded travelled distance and others elapsed time, thus refuting the notion that all hippocampal cells were performing path integration. Using the data from these experiments, we asked whether the two populations depended on the type of task the rats were engaged in. We show that the type of experiment determined the cells’ encoding, such that in fixed-distance experiments distance-encoding cells dominated, while on fixed-time experiments time-encoding cells dominated. These results suggest that the cells’ encoding contains a predictive element, dependent on the important variables of the experiment.
Auditory Brainstem Response as an Objective Measure of Temporal Resolution
Authors: Athreya Varsha M , Barman Animesh 
Published: October 2022

AbstractBackground and AimsTemporal resolution is assessed using behavioral tests, which are highly affected by extraneous variables. We explored the relationship between behavioral Across-Channel Gap Detection Threshold (AC GDT) and different temporal parameters of an objective measure, Auditory Brainstem Response (ABR), to account for the extraneous variables.Settings and DesignWe conducted an experimental study on thirty native Kannada-speaking adults with normal hearing sensitivity in the age range of 18-25 years.Materials and MethodsWe estimated the Gap detection threshold (GDT) using an across-channel (AC) paradigm, and Auditory Brainstem Response (ABR) was recorded at 80 dBnHL for three repetition rates of 11.1, 30.1, and 90.1/sec.Statistical Analyses usedNormality testing, the Friedman test, post-hoc analysis by Wilcoxon Signed-Rank test, along with descriptive statistics was performed using SPSS v20 (IBM Statistical Package for Social Sciences, New York, USA).ResultsThe results showed a significant positive correlation between AC GDT scores and latency of wave I for the repetition rates of 11.1 and 30.1/sec and latency of wave V at 30.1 and 90.1/sec. There was a negative correlation (but not significant) between AC GDT scores and the slope of wave V across the repetition rates.ConclusionsThe results suggest a relationship between the behavioral and electrophysiological measures of temporal processing. Measuring the latency of wave I and wave V of ABR would give an estimate of their AC GDT scores, especially in difficult-to-test populations.Key messagesTo test temporal resolution abilities in individuals with normal hearing sensitivity, we can use an objective measure of latency of wave I and wave V of ABR. ABR can be highly useful in reducing testing time and obtaining reliable estimates in children and individuals with associated disorders like autism, below-average intelligence, and so on.
Enhancing HIV-1 neutralization by increasing the local concentration of MPER-directed bnAbs
Authors: Kim Soohyun , Interrante Maria V. Filsinger , Kim Peter S. 
Published: October 2022

AbstractBroadly neutralizing antibodies (bnAbs) against the membrane-proximal external region (MPER) of the gp41 component of the HIV-1 envelope (Env) are characterized by long hydrophobic heavy-chain complementarity-determining regions (HCDR3s) that interact with MPER and some viral membrane lipids, to achieve increased local concentrations. Here, we show that increasing the local concentration of MPER-directed bnAbs at the cell surface via binding to the high affinity Fc receptor (FcγRI) potentiates their ability to prevent viral entry in a manner analogous to the previously reported observation whereby the lipid binding activity of MPER bnAbs increases their concentration at the viral surface membrane. However, binding of MPER-directed bnAb 10E8 to FcγRI abolishes the neutralization synergy that is seen with the N-heptad repeat (NHR)-targeting antibody D5_AR and NHR-targeting small molecule enfuvirtide (T20), possibly due to decreased accessibility of the NHR in the FcγRI-10E8-MPER complex. Taken together, our results suggest that lipid-binding activity and FcγRI-mediated potentiation function in concert to improve the potency of MPER-directed bnAbs by increasing their local concentration near the site of viral fusion. Therefore, lipid-binding may not be a strict requirement for potent neutralization by MPER-targeting bnAbs, as alternative methods can achieve similar increase in local concentration while avoiding potential liabilities associated with immunologic host tolerance.Author summaryThe trimeric glycoprotein Env is the only viral protein expressed on the surface of HIV-1, is the target of broadly neutralizing antibodies, and is the focus of most vaccine development efforts. Broadly neutralizing antibodies targeting the membrane proximal external region (MPER) of Env show lipid-binding characteristics and modulating this interaction affects neutralization. In this study, we tested the neutralization potencies of variants of the MPER-targeting antibody 10E8 with different viral membrane-binding and host FcγRI-binding capabilities. Our results suggest that binding to both lipid and FcγRI improves the neutralization potency of MPER-directed antibodies by concentrating the antibody at sites of viral fusion. As such, lipid-binding may not be uniquely required for MPER-targeting broadly neutralizing antibodies, as alternative methods to increase local concentration can achieve similar improvements in potency.