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  1. Article ; Online: A nonanalog Pliocene ungulate community at Laetoli with implications for the paleoecology of Australopithecus afarensis.

    Fillion, Elizabeth N / Harrison, Terry / Kwekason, Amandus

    Journal of human evolution

    2022  Volume 167, Page(s) 103182

    Abstract: The dietary guild structure of ungulate communities is a useful paleoecological tool for understanding the context of hominin paleobiology and evolution. Ungulates are well represented in the fossil record, and their dietary preferences reflect those of ... ...

    Abstract The dietary guild structure of ungulate communities is a useful paleoecological tool for understanding the context of hominin paleobiology and evolution. Ungulates are well represented in the fossil record, and their dietary preferences reflect those of major habitat types. However, paleoecology relies on modern ecological patterns as analogs for recreating ecologies of the past. It has previously been suggested that for much of the Pliocene, no such modern analogs exist for the herbivore communities associated with hominins in eastern Africa. This study aims to determine whether the ungulate community associated with A. afarensis at the Pliocene site of Laetoli, Tanzania, shares similarities with extant communities or whether it lacks a modern analog. Our multiproxy approach using mesowear, hypsodonty, and stable carbon isotopes of tooth enamel to infer the diets of ungulates in the Upper Laetolil Beds shows that this community is dominated by browsers and mixed feeders and has a very low prevalence of grazers and frugivores. This dietary guild composition distinguishes the Upper Laetolil Beds from modern African communities and suggests either that the Upper Laetolil Beds had a unique vegetation structure which was able to support a higher diversity of browsing ungulates than that exists in African ecosystems today or that it retained an ungulate community that was resilient to environmental change. The Upper Laetolil Beds ungulate community is also unique relative to other mid-Pliocene communities in eastern Africa, some of which are similar to extant communities, while others, such as Laetoli, lack modern counterparts. This suggests that A. afarensis was a eurytopic species that inhabited a variety of ecosystems, including those with and without modern analogs. The co-occurrence of both analog and nonanalog communities in the Pliocene suggests that the transformation toward ungulate communities of modern aspect occurred asynchronously in eastern Africa.
    MeSH term(s) Animals ; Ecosystem ; Fossils ; Hominidae ; Mammals ; Tanzania
    Language English
    Publishing date 2022-04-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 120141-4
    ISSN 1095-8606 ; 0047-2484
    ISSN (online) 1095-8606
    ISSN 0047-2484
    DOI 10.1016/j.jhevol.2022.103182
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  2. Article ; Online: Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.

    Coleman, Daniel J L / Keane, Peter / Chin, Paulynn S / Ames, Luke / Kellaway, Sophie / Blair, Helen / Khan, Naeem / Griffin, James / Holmes, Elizabeth / Maytum, Alexander / Potluri, Sandeep / Strate, Lara / Koscielniak, Kinga / Raghavan, Manoj / Bushweller, John / Heidenreich, Olaf / Rabbitts, Terry / Cockerill, Peter N / Bonifer, Constanze

    iScience

    2024  Volume 27, Issue 4, Page(s) 109576

    Abstract: AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and ... ...

    Abstract AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2024.109576
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  3. Article: Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

    Abbas-Aghababazadeh, Farnoosh / Sasamoto, Naoko / Townsend, Mary K / Huang, Tianyi / Terry, Kathryn L / Vitonis, Allison F / Elias, Kevin M / Poole, Elizabeth M / Hecht, Jonathan L / Tworoger, Shelley S / Fridley, Brooke L

    Frontiers in oncology

    2023  Volume 13, Page(s) 1090092

    Abstract: ... epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ...

    Abstract Objective: Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery.
    Methods: Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC).
    Results: Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62).
    Conclusions: Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.
    Language English
    Publishing date 2023-01-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1090092
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  4. Article ; Online: Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

    Li, Shouqiang / Chen, Cheng / Lof, John / Stolze, Elizabeth A / Sklenar, Jiri / Chen, Xucai / Pacella, John J / Villanueva, Flordeliza S / Matsunaga, Terry O / Everbach, E Carr / Radio, Stanley J / Westphal, Sherry N / Shiva, Sruti / Xie, Feng / Leng, Xiaoping / Porter, Thomas R

    Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine

    2024  

    Abstract: Background: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within ... ...

    Abstract Background: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ).
    Objective: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region.
    Methods: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity.
    Results: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01).
    Conclusions: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.
    Language English
    Publishing date 2024-03-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 604829-8
    ISSN 1550-9613 ; 0278-4297
    ISSN (online) 1550-9613
    ISSN 0278-4297
    DOI 10.1002/jum.16435
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  5. Article ; Online: Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

    Breen, William G / Geno, Connie S / Waddle, Mark R / Qian, Jing / Harmsen, William S / Burns, Terry C / Sener, Ugur T / Ruff, Michael W / Neth, Bryan J / Uhm, Joon H / Routman, David M / Yan, Elizabeth / Kruse, Jon J / Laack, Nadia N / Brown, Paul D / Mahajan, Anita

    Neuro-oncology advances

    2024  Volume 6, Issue 1, Page(s) vdae034

    Abstract: Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients.: Methods: This single-institution retrospective analyzed ... ...

    Abstract Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients.
    Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients.
    Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all
    Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.
    Language English
    Publishing date 2024-03-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 3009682-0
    ISSN 2632-2498 ; 2632-2498
    ISSN (online) 2632-2498
    ISSN 2632-2498
    DOI 10.1093/noajnl/vdae034
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  6. Article ; Online: Post-Covid-19 condition (Long Covid) in children and young people 12 months after infection or reinfection with the Omicron variant: a prospective observational study.

    Pinto Pereira, Snehal M / Nugawela, Manjula D / Stephenson, Terence / Foret-Bruno, Paul / Dalrymple, Emma / Xu, Laila / Whittaker, Elizabeth / Heyman, Isobel / Ford, Tamsin / Segal, Terry / Chalder, Trudie / Ladhani, Shamez N / Mensah, Anna A / McOwat, Kelsey / Simmons, Ruth / Shafran, Roz

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 9957

    Abstract: Our previous study in children and young people (CYP) at 3- and 6-months post-infection showed that 12-16% of those infected with the Omicron (B.1.1.529) variant of SARS-CoV-2 met the research definition of Long Covid, with no differences between first- ... ...

    Abstract Our previous study in children and young people (CYP) at 3- and 6-months post-infection showed that 12-16% of those infected with the Omicron (B.1.1.529) variant of SARS-CoV-2 met the research definition of Long Covid, with no differences between first-positive and reinfected CYP. The primary objective of the current study is to explore the impact of the Omicron variant of SARS-CoV-2 infection on young people 12 months post infection. 345 CYP aged 11-17 years with a first laboratory-confirmed infection with the Omicron variant and 360 CYP reinfected with the Omicron variant completed an online questionnaire assessing demographics, symptoms, and their impact shortly after testing and again at 3-, 6-and 12-months post-testing. Vaccination status was determined from information held at UKHSA. Comparisons between groups were made using chi-squared, Mann-Whitney U, and Kruskal-Wallis tests. The most common symptoms in first-positive and reinfected CYP 12-months post-testing were tiredness (35.7 and 33.6% respectively) and sleeping difficulties (27.5 and 28.3% respectively). Symptom profiles, severity and impact were similar in the two infection status groups. Overall, by 12-months, 17.4% of first-positives and 21.9% of reinfected CYP fulfilled the research consensus Long Covid definition (p = 0.13). 12-months post Omicron infection, there is little difference between first-positive and reinfected CYP with respect to symptom profiles and impact. Clinicians may not therefore need to consider number of infections and type of variant when developing treatment plans. Further studies are needed to assess causality of reported symptoms up to 12-months after SARS-CoV-2 infection.
    MeSH term(s) Humans ; COVID-19/virology ; COVID-19/complications ; COVID-19/epidemiology ; Child ; SARS-CoV-2/isolation & purification ; Adolescent ; Male ; Female ; Reinfection/virology ; Prospective Studies ; Post-Acute COVID-19 Syndrome
    Language English
    Publishing date 2024-04-30
    Publishing country England
    Document type Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-60372-4
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  7. Article ; Online: The relationship between Post COVID symptoms in young people and their parents.

    Bertran, Marta / Pinto Pereira, Snehal M / Nugawela, Manjula D / Stephenson, Terence / Shafran, Roz / Ford, Tamsin / Buszewicz, Marta / Whittaker, Elizabeth / Heyman, Isobel / Segal, Terry Y / Dalrymple, Emma / Ladhani, Shamez N

    The Journal of infection

    2022  Volume 85, Issue 6, Page(s) 702–769

    MeSH term(s) Humans ; Adolescent ; COVID-19 ; Parents
    Language English
    Publishing date 2022-10-08
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 424417-5
    ISSN 1532-2742 ; 0163-4453
    ISSN (online) 1532-2742
    ISSN 0163-4453
    DOI 10.1016/j.jinf.2022.10.005
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  8. Article ; Online: Physical activity and mental well-being under COVID-19 lockdown: a cross-sectional multination study.

    Karageorghis, Costas I / Bird, Jonathan M / Hutchinson, Jasmin C / Hamer, Mark / Delevoye-Turrell, Yvonne N / Guérin, Ségolène M R / Mullin, Elizabeth M / Mellano, Kathleen T / Parsons-Smith, Renée L / Terry, Victoria R / Terry, Peter C

    BMC public health

    2021  Volume 21, Issue 1, Page(s) 988

    Abstract: ... quarter of 2020 (N = 2541). We measured planned and unplanned dimensions of PA using the Brunel Lifestyle ...

    Abstract Background: COVID-19 lockdowns have reduced opportunities for physical activity (PA) and encouraged more sedentary lifestyles. A concomitant of sedentariness is compromised mental health. We investigated the effects of COVID-19 lockdown on PA, sedentary behavior, and mental health across four Western nations (USA, UK, France, and Australia).
    Methods: An online survey was administered in the second quarter of 2020 (N = 2541). We measured planned and unplanned dimensions of PA using the Brunel Lifestyle Physical Activity Questionnaire and mental health using the 12-item General Health Questionnaire. Steps per day were recorded only from participants who used an electronic device for this purpose, and sedentary behavior was reported in hours per day (sitting and screen time).
    Results: In the USA and Australia samples, there was a significant decline in planned PA from pre- to during lockdown. Among young adults, Australians exhibited the lowest planned PA scores, while in middle-aged groups, the UK recorded the highest. Young adults exhibited the largest reduction in unplanned PA. Across nations, there was a reduction of ~ 2000 steps per day. Large increases in sedentary behavior emerged during lockdown, which were most acute in young adults. Lockdown was associated with a decline in mental health that was more pronounced in women.
    Conclusions: The findings illustrate the deleterious effects of lockdown on PA, sedentary behavior, and mental health across four Western nations. Australian young and lower middle-aged adults appeared to fare particularly badly in terms of planned PA. The reduction in steps per day is equivalent to the non-expenditure of ~ 100 kcal. Declines in mental health show how harmful lockdowns can be for women in particular.
    MeSH term(s) Australia ; COVID-19 ; Communicable Disease Control ; Cross-Sectional Studies ; Exercise ; Female ; France ; Humans ; Mental Health ; Middle Aged ; SARS-CoV-2 ; Young Adult
    Language English
    Publishing date 2021-05-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041338-5
    ISSN 1471-2458 ; 1471-2458
    ISSN (online) 1471-2458
    ISSN 1471-2458
    DOI 10.1186/s12889-021-10931-5
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  9. Article ; Online: COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis.

    Rebello, Denise / Wohler, Elizabeth / Erfani, Vida / Li, Guozhuang / Aguilera, Alexya N / Santiago-Cornier, Alberto / Zhao, Sen / Hwang, Steven W / Steiner, Robert D / Zhang, Terry Jianguo / Gurnett, Christina A / Raggio, Cathleen / Wu, Nan / Sobreira, Nara / Giampietro, Philip F / Ciruna, Brian

    Human molecular genetics

    2023  Volume 32, Issue 19, Page(s) 2913–2928

    Abstract: Human vertebral malformations (VMs) have an estimated incidence of 1/2000 and are associated with significant health problems including congenital scoliosis (CS) and recurrent organ system malformation syndromes such as VACTERL (vertebral anomalies; anal ...

    Abstract Human vertebral malformations (VMs) have an estimated incidence of 1/2000 and are associated with significant health problems including congenital scoliosis (CS) and recurrent organ system malformation syndromes such as VACTERL (vertebral anomalies; anal abnormalities; cardiac abnormalities; tracheo-esophageal fistula; renal anomalies; limb anomalies). The genetic cause for the vast majority of VMs are unknown. In a CS/VM patient cohort, three COL11A2 variants (R130W, R1407L and R1413H) were identified in two patients with cervical VM. A third patient with a T9 hemivertebra and the R130W variant was identified from a separate study. These substitutions are predicted to be damaging to protein function, and R130 and R1407 residues are conserved in zebrafish Col11a2. To determine the role for COL11A2 in vertebral development, CRISPR/Cas9 was used to create a nonsense mutation (col11a2L642*) as well as a full gene locus deletion (col11a2del) in zebrafish. Both col11a2L642*/L642* and col11a2del/del mutant zebrafish exhibit vertebral fusions in the caudal spine, which form due to mineralization across intervertebral segments. To determine the functional consequence of VM-associated variants, we assayed their ability to suppress col11a2del VM phenotypes following transgenic expression within the developing spine. While wildtype col11a2 expression suppresses fusions in col11a2del/+ and col11a2del/del backgrounds, patient missense variant-bearing col11a2 failed to rescue the loss-of-function phenotype in these animals. These results highlight an essential role for COL11A2 in vertebral development and support a pathogenic role for two missense variants in CS.
    MeSH term(s) Animals ; Humans ; Scoliosis/genetics ; Zebrafish/genetics ; Spine/abnormalities ; Abnormalities, Multiple/genetics ; Mutation, Missense ; Collagen Type XI/genetics
    Chemical Substances COL11A2 protein, human ; Collagen Type XI
    Language English
    Publishing date 2023-07-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddad117
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  10. Article ; Online: Pathogenic Mechanisms of Cytosolic and Membrane-Enriched α-Synuclein Converge on Fatty Acid Homeostasis.

    Tripathi, Arati / Alnakhala, Heba / Terry-Kantor, Elizabeth / Newman, Andrew / Liu, Lei / Imberdis, Thibaut / Fanning, Saranna / Nuber, Silke / Ramalingam, Nagendran / Selkoe, Dennis / Dettmer, Ulf

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2022  Volume 42, Issue 10, Page(s) 2116–2130

    Abstract: ... we examine two clinical mutants, E46K and G51D, which are both in the conserved N-terminus that mediates ...

    Abstract α-Synuclein (αS) plays a key role in Parkinson's disease. Although Parkinson's disease is typically "sporadic," inherited αS missense mutations provide crucial insights into molecular mechanisms. Here, we examine two clinical mutants, E46K and G51D, which are both in the conserved N-terminus that mediates transient αS-membrane interactions. However, E46K increases and G51D decreases αS-membrane interactions. Previously, we amplified E46K via the 11-residue repeat motifs, creating "3K" (E35K+E46K+E61K). Here, we engineered these motifs to amplify G51D (V40D+G51D+V66D = "3D") and systematically compared E46K/3K versus G51D/3D. We found that G51D increased cytosolic αS in neural cells and 3D aggravates this. G51D, and 3D even more, reduced αS multimer-to-monomer (αS60:αS14) ratio. Both amplified variants caused cellular stress in rat primary neurons and reduced growth in human neuroblastoma cells. Importantly, both 3K- and 3D-induced stress was ameliorated by pharmacologically inhibiting stearoyl-CoA desaturase or by conditioning the cells in palmitic (16:0) or myristic (14:0) acid. SCD inhibition lowered lipid-droplet accumulation in both 3D- and 3K-expressing cells and benefitted G51D by normalizing multimer:monomer ratio, as reported previously for E46K. Our findings suggest that, despite divergent cytosol/membrane partitioning, both G51D and E46K neurotoxicity can be prevented by decreasing fatty-acid unsaturation as a common therapeutic approach.
    MeSH term(s) Animals ; Cytosol/metabolism ; Fatty Acids/metabolism ; Homeostasis ; Parkinson Disease/metabolism ; Rats ; Stearoyl-CoA Desaturase/metabolism ; alpha-Synuclein/metabolism
    Chemical Substances Fatty Acids ; alpha-Synuclein ; Stearoyl-CoA Desaturase (EC 1.14.19.1)
    Language English
    Publishing date 2022-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.1881-21.2022
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