bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional and effective connectivity between dorsolateral prefrontal and subgenual anterior cingulate cortex depends on the timing of transcranial magnetic stimulation relative to the phase of prefrontal alpha EEG
Authors: Pantazatos Spiro P. , Mclntosh James R. , Saber Golbarg T. , Sun Xiaoxiao , Doose Jayce , Faller Josef , Lin Yida , Teves Joshua B. , Blankenship Aidan , Huffman Sarah , Goldman Robin I. , George Mark S. , Sajda Paul , Brown Truman R. 
Published: February 2022

ABSTRACTBACKGROUNDThe communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited.METHODSHere, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Results in healthy volunteers (n=11) were compared to those from patients with major depressive disorder (MDD) (n=17) collected as part of a ongoing clinical trial investigation.RESULTSIn both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC effective connectivity (EC) was moderated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS onsets during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group.DISCUSSIONResults demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest clinical applications whereby TMS is synchronized to the brain’s internal rhythms in order to more efficiently engage deep therapeutic targets.
Validation of the RT-LAMP assay in a large cohort of nasopharyngeal swab samples shows that it is a useful screening method for detecting SARS-CoV-2 and its VOC variants
Authors: Cisneros-Villanueva Mireya , Blancas Sugela , Cedro-Tanda Alberto , Ríos-Romero Magdalena , Hurtado-Córdova Eduardo , Almaraz-Rojas Oscar , Ortiz-Soriano Diana R. , Álvarez-Hernández Víctor , Arriaga-Guzmán Ivonne E. , Tolentino-García Laura , Sánchez-Vizcarra Antonia , Lozada-Rodríguez Laura F. , Peralta-Arrieta Irlanda , Pérez-Aquino José E. , Andonegui-Elguera Marco A. , Cendejas-Orozco Mariana , Mendoza-Vargas Alfredo , Reyes-Grajeda Juan P. , Campos-Romero Abraham , Alcantar-Fernández Jonathan , Luis Moreno-Camacho José , Gallegos-Rodriguez Jorge , Esparza-Luna-Ruiz Marco , Ortiz-Ramirez Jesus , Gonzalez Mariana Benitez , Uribe-Figueroa Laura , Ruiz Rosaura , Angulo Ofelia , Herrera Luis A. , Hidalgo-Miranda Alfredo 
Published: February 2022

AbstractThe COVID-19 pandemic is challenging the global supply chain and equipment needed for mass testing with RT-qPCR, the gold standard for SARS-CoV-2 diagnosis. Here, we propose the RT-LAMP assay as an additional strategy for rapid virus diagnosis. However, its validation as a diagnostic method remains uncertain. In this work, we validated the RT-LAMP assay in 1,266 nasopharyngeal swab samples with confirmed diagnosis by CDC 2019-nCoV RT-qPCR. Our cohort was divided, the first (n=984) was used to evaluate two sets of oligonucleotides (S1 and S3) and the second (n=281) to determine whether RT-LAMP could detect samples with several types of variants. This assay can identify positive samples by color change or fluorescence within 40 minutes and shows high concordance with RT-qPCR in samples with CT ≤35. Also, S1 and S3 are able to detect SARS-CoV-2 with a sensitivity of 68.4% and 65.8%, and a specificity of 98.9% and 97.1%, respectively. Furthermore, RT-LAMP assay identified 279 sequenced samples as positive (99.3% sensitivity) corresponding to the Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda, Mu and Omicron variants. In conclusion, RT-LAMP is able to identify SARS-CoV-2 with good sensitivity and excellent specificity, including all VOC, VOI, VUM and FMV variants.
Sequential increase of PHGDH expression with Alzheimer’s pathology and symptoms
Authors: Chen Xu , Calandrelli Riccardo , Girardini John , Yan Zhangming , Tan Zhiqun , Xu Xiangmin , Hiniker Annie , Zhong Sheng 
Published: February 2022

AbstractWe report consistent increases in phosphoglycerate dehydrogenase (PHGDH) expression in mouse models of Alzheimer’s disease (AD) (3xTg-AD) and related tauopathy (PS19), particularly in hippocampal astrocytes. Human single-cell RNA-sequencing data reveal a sequential increase of PHGDH expression in people with no, early, and late AD pathology, which is corroborated by protein mass spectrometry and immunohistochemical analyses of three independent cohorts. A sequential increase of PHGDH expression also correlates with increasing clinical AD symptoms and worsening cognitive decline in patients. The consistent increase of PHGDH expression in six AD cohorts (Mayo, ROSMAP, Mount Sinai, Baltimore, Amsterdam, and UCSD/UCI) corroborates with the recent report of PHGDH extracellular RNA in blood plasma as a candidate biomarker for early diagnosis of AD and offers a caution to the suggested use of L-serine as a potential therapy of AD.
Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation
Authors: Petrauskas Arnas , Fortunati Daniel L. , Singh Amanjot , Kandi Arvind Reddy , Pothapragada Sai Shruti , Agrawal Khushboo , Huelsmeier Joern , Hillebrand Jens , Brown Georgia , Chaturvedi Dhananjay , Lee Jongbo , Lim Chunghun , Auburger Georg , VijayRaghavan K. , Ramaswami Mani , Bakthavachalu Baskar 
Published: February 2022

ABSTRACTAtaxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments onDrosophilaand human Ataxin-2 proteins. Results of Targets of RNA-Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Transgenic experiments inDrosophilaindicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.
International spread of emerging multidrug-resistant Rhodococcus equi
Authors: Val-Calvo Jorge , Darcy Jane , Gibbons James , Creighton Alan , Egan Claire , Buckley Thomas , Schmalenberger Achim , Fogarty Ursula , Scortti Mariela , Vázquez-Boland José A. 
Published: February 2022

AbstractThe recently characterized multidrug-resistant clone of the animal and human zoonotic pathogen Rhodococcus equi, MDR-RE 2287, has been circulating among horse farms in the United States (US) since the early 2000’s. Here, we report the first documented detection of the MDR-RE 2287 clone outside the US. The finding highlights the risk of MDR-RE spreading internationally with the movement of horses.
Contribution of individual excitatory synapses on dendritic spines to electrical signalling
Authors: Weng Ju-Yun , Ceballos Cesar , Zecevic Dejan 
Published: February 2022

AbstractDendritic spines, small (∼1 µm) membrane protrusions from neuronal dendrites which receive most of the excitatory synaptic inputs in the mammalian brain, are widely considered the elementary computational units of the brain. Our understanding of electrical signalling in spines is currently being debated, primarily for methodological reasons. We combined the standard techniques of whole-cell recording and voltage imaging methods to study excitatory postsynaptic potentials evoked by two-photon glutamate uncaging (uEPSPs) on individual dendritic spines on basal dendrites in rat cortical slices. We analyzed the initiation, temporal summation, and propagation of uEPSPs from the spine head to the parent dendrites in three principal neocortical pyramidal neuron classes. Our measurements show no significant attenuation of uEPSPs across the spine neck in most tested mushroom spines on basal dendrites. This result implies that spine synapses are not electrically isolated from parent dendrites and that these spines do not serve a meaningful electrical role. Using the same high-sensitivity voltage imaging techniques, we characterized the temporal summation of uEPSPs induced by repetitive glutamate uncaging mimicking burst activity of presynaptic neurons. We found that responses to high-frequency repetitive quantal EPSPs are strictly limited in amplitude and waveform. This finding reveals a biophysical mechanism for preventing synaptic saturation.Significance StatementWe used an electrochromic voltage-sensitive dye, which acts as a transmembrane optical voltmeter, to define the electrical role of dendritic spines, small membrane protrusions that receive most of the excitatory synaptic inputs in the brain. The data argue that investigated spine synapses of principal neurons are not electrically isolated from the parent dendrites. We also found that the amplitude of temporal uEPSP summation during repetitive synaptic activation is restricted at the site of origin, preventing synaptic saturation. These results facilitate our understanding of how a complex assembly of receptors and ion channels in spines generates and processes electrical signals and mediate plasticity in response to the quantal release of chemical transmitters caused by patterned activity in presynaptic axons.
Antibacterial potency of Type VI amidase effector toxins is dependent on substrate topology and cellular context
Authors: Radkov Atanas , Sapiro Anne L , Flores Sebastian , Henderson Corey , Saunders Hayden , Kim Rachel , Massa Steven , Thompson Samuel , Mateusiak Chase , Biboy Jacob , Zhao Ziyi , Starita Lea M. , Hatleberg William , Vollmer Waldemar , Russell Alistair B. , Simorre Jean-Pierre , Anthony-Cahill Spencer , Brzovic Peter , Hayes Beth , Chou Seemay 
Published: February 2022

AbstractMembers of the bacterialT6SSamidaseeffector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 fromPseudomonas aeruginosaPAO1 using a combination ofnuclearmagnetic resonance (NMR) and a high-throughputin vivogenetic approach calleddeepmutationalscanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape oftae1toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.
The Conserved CNOT1 Interaction Motif of Tristetraprolin Regulates ARE-mRNA Decay Independently of the p38 MAPK-MK2 Kinase Pathway
Authors: Carreño Alberto , Lykke-Andersen Jens 
Published: February 2022

SummaryRegulation of the mRNA decay activator Tristetraprolin (TTP) by the p38 mitogen-activated protein kinase (MAPK) pathway during the mammalian inflammatory response represents a paradigm for the regulation of mRNA turnover by signaling. Phosphorylation of TTP by p38 MAPK-activated kinase 2 (MK2) inhibits the association of TTP with the CCR4-NOT deadenylase complex and represses TTP-mediated mRNA decay. Here we present evidence that TTP remains active in the presence of activated MK2 due to its highly conserved CNOT1 Interacting Motif (CIM), which remains unphosphorylated and capable of promoting deadenylation and decay. The CIM recruits the CCR4-NOT complex cooperatively with previously identified conserved tryptophan residues of TTP and deletion of the CIM strongly represses residual association with the deadenylase complex and activity of TTP in conditions of active MK2. A conserved serine in the CIM is not a target of MK2 but is instead phosphorylated by other kinases including the PKCα pathway and regulates TTP activity independently of MK2. These results suggest that kinase pathways regulate TTP activity in a cooperative manner and that the p38 MAPK-MK2 pathway relies on the activation of additional kinase pathway(s) to fully control TTP function.
City-wide wastewater genomic surveillance through the successive emergence of SARS-CoV-2 Alpha and Delta variants
Authors: Brunner F.S. , Brown M.R. , Bassano I. , Denise H. , Khalifa M.S. , Wade M. , Kevill J.L. , Jones D.L. , Farkas K. , Jeffries A.R. ,   The COVID-19 Genomics UK (COG-UK) Consortium, Cairns E. , Wierzbicki C. , Paterson S. 
Published: February 2022

AbstractGenomic surveillance of SARS-CoV-2 has been essential to provide an evidence base for public health decisions throughout the SARS-CoV-2 pandemic. Sequencing data from clinical cases has provided data crucial to understanding disease transmission and the detection, surveillance, and containment of outbreaks of novel variants, which continue to pose fresh challenges. However, genomic wastewater surveillance can provide important complementary information by providing estimates of variant frequencies which do not suffer from sampling bias, and capturing all variants circulating in a population. Here we show that genomic SARS-CoV-2 wastewater surveillance can detect fine-scale differences within urban centres, specifically within the city of Liverpool, UK, during the emergence of Alpha and Delta variants between November 2020 and June 2021. Overall, the correspondence between wastewater and clinical variant frequencies demonstrates the reliability of wastewater surveillance. Yet, discrepancies between the two approaches when the Alpha variant was first detected emphasises that wastewater monitoring can also capture missing information resulting from asymptomatic cases or communities less engaged with testing programmes, as found by a simultaneous surge testing effort across the city.
The SARS-CoV2 envelope is distinct from host membranes, exposes pro-coagulant lipids, and can be inactivated in vivo by surfactant-containing oral rinses
Authors: Saud Zack , Tyrrell Victoria J , Zaragkoulias Andreas , Protty Majd B , Statkute Evelina , Rubina Anzelika , Bentley Kirsten , White Daniel A. , Santos Rodrigues Patricia Dos , Murphy Robert C , Köfeler Harald , Griffiths William J , Alvarez-Jarreta Jorge , Brown Richard William , Newcombe Robert G , Heyman James , Pritchard Manon , Mcleod Robert WJ , Arya Arvind , Lynch Ceri-Ann , Owens David , Jenkins P Vince , Buurma Niklaas J. , O’Donnell Valerie B , Thomas David W. , Stanton Richard J. 
Published: February 2022

AbstractThe lipid envelope of SARS-CoV2 is an essential component of the virus, however its molecular composition is unknown. Addressing this knowledge gap could support the design of anti-viral agents, and further understanding of viral interaction with extracellular host proteins, infectivity, pathogenicity, and innate immune system clearance. Lipidomics analysis of SARS-CoV2 particles generated from Vero or A549 cells revealed that the virus envelope comprised mainly of phospholipids (PL), primarily phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI), with very little cholesterol, sphingolipids or other lipids, indicating significant differences from host membranes. Unlike healthy cellular membranes, procoagulant aminoPL (aPL), specifically PE and phosphatidylserine (PS), were present on the external side at levels far exceeding those seen on activated platelets. As a result, purified virions directly promoted coagulation. To investigate whether these differences enabled the viral envelope to be selectively targeted at relevant sites in vivo, we tested whether non-toxic oral rinses containing lipid disrupting chemicals could reduce viral infectivity. Products containing PL-disrupting surfactant solutions (cetylpyridinium chloride (CPC) or ethyl lauroyl arginate) met EN14476 virucidal standards in vitro, however products containing essential oils, PVP-I, or Chlorhexidine did not, nor did rinses containing components that altered the critical micelle concentration of CPC. This result was recapitulated in vivo, where a 30-second oral rinse with CPC-mouthwash eliminated live virus in the oral cavity of COVID19 patients for at least 1hr, while PVP-Iodine and saline mouthwashes were ineffective. Thus, the SARS-CoV2 lipid envelope is distinct from the host plasma membrane which may enable design of selective anti-viral approaches, it exposes PE and PS which may influence thrombosis, pathogenicity, and inflammation, and can be selectively targeted in vivo by specific oral rinses.
Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking
Authors: Xue Xiaohan , Buccino Alessio Paolo , Kumar Sreedhar Saseendran , Hierlemann Andreas , Bartram Julian 
Published: February 2022

AbstractTechniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.
A small molecule probe elucidates the role of mitochondrial translocase TIMM44 in PINK1/Parkin regulated mitophagy
Authors: Conti Michael A. , Torres Eric , van der Bliek Alexander M. , Koehler Carla M. 
Published: February 2022

AbstractNeurodegenerative diseases have been linked to a dysfunctional mitochondrial quality control system that is partially maintained by proteins PINK1 and Parkin. Whereas mitophagy pathways are becoming well-characterized, less is known about the molecular mechanisms of PINK1 trafficking in mitochondria. Accordingly, we have used a small molecule probe (MitoBloCK-10/MB-10) that modulates the activity of TIMM44, an essential component of the protein associated motor (PAM) complex for the mitochondrial inner membrane (TIM23) translocase, to characterize PINK1 import. MB-10 did not inhibit the import or degradation of PINK1 in energized mitochondria. However, when mitophagy was induced by the addition of an uncoupler or respiratory inhibitor, MB-10 treatment altered PINK1 trafficking by inhibiting association with the TOM complex and impairing Parkin recruitment and subsequent mitophagy. MB-10 analogs that did not inhibit TIMM44 activity failed to impair mitophagy, thereby assigning specificity to MB-10. Because PINK1 undergoes lateral release from the TIM23 translocon to interact with inner membrane (IM) modulators, our studies support that TIMM44 may be a key regulator and that the PAM complex has a central role in regulating PINK1-dependent mitophagy. Our studies also provide a probe for dissecting PINK1/Parkin events for mitochondria as well as studying PINK1-dependent mitophagy in cell and animal models.
GWAS in the southern African context
Authors: Swart Yolandi , van Eeden Gerald , Uren Caitlin , van der Spuy Gian , Tromp Gerard , Möller Marlo 
Published: February 2022

AbstractResearchers would generally adjust for the possible confounding effect of population structure by considering global ancestry proportions or top principle components. Alternatively, researchers would conduct admixture mapping to increase the power to detect variants with an ancestry effect. This is sufficient in simple admixture scenarios, however, populations from southern Africa can be complex multi-way admixed populations. Duanet al. (2018) first described local ancestry adjusted allelic (LAAA) analysis as a robust method for discovering association signals, while producing minimal false-positives. Their simulation study, however, was limited to a two-way admixed population. Realizing that their findings might not translate to other admixture scenarios, we simulated a three- and five-way admixed population to compare the LAAA model to other models commonly used in GWAS. We found that, given our admixture scenarios, the LAAA model identifies the most causal variants in most of the phenotypes we tested across both the three-way and five-way admixed populations. The LAAA model also produced a high number of false-positives which was potentially caused by the ancestry effect size that we assumed. Considering the extent to which the various models tested differed in their results and considering that the source of a given association is unknown, we recommend that researchers use multiple GWAS models when analysing populations with complex ancestry.