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Article ; Online: Postnatal Zika virus infection leads to morphological and cellular alterations within the neurogenic niche.

Ferreira, Jéssica C C G / Christoff, Raissa R / Rabello, Tailene / Ferreira, Raiane O / Batista, Carolina / Mourão, Pedro Junior Pinheiro / Rossi, Átila D / Higa, Luiza M / Bellio, Maria / Tanuri, Amilcar / Garcez, Patricia P

Disease models & mechanisms

2024 Volume 17, Issue 2

Abstract: The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to ...

Abstract	The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital Zika syndrome. Contrastingly, much less is known about how neonatal infection affects the development of the newborn nervous system. Here, we investigated the development of the dentate gyrus of wild-type mice following intracranial injection of the virus at birth (postnatal day 0). Through this approach, we found that Zika virus infection affected the development of neurogenic regions within the dentate gyrus and caused reactive gliosis, cell death and a decrease in cell proliferation. Such infection also altered volumetric features of the postnatal dentate gyrus. Thus, we found that Zika virus exposure to newborn mice is detrimental to the subgranular zone of the dentate gyrus. These observations offer insight into the cellular mechanisms that underlie the neurological features of congenital Zika syndrome in children.
MeSH term(s)	Humans ; Child ; Infant ; Female ; Pregnancy ; Animals ; Mice ; Zika Virus Infection/complications ; Zika Virus ; Neurogenesis ; Cell Death ; Cell Proliferation
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050375
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Article ; Online: Congenital Zika Virus Infection Impairs Corpus Callosum Development.

Christoff, Raissa Rilo / Quintanilha, Jefferson H / Ferreira, Raiane Oliveira / Ferreira, Jessica C C G / Guimarães, Daniel Menezes / Valério-Gomes, Bruna / Higa, Luiza M / Rossi, Átila D / Bellio, Maria / Tanuri, Amilcar / Lent, Roberto / Garcez, Patricia Pestana

Viruses

2023 Volume 15, Issue 12

Abstract: Congenital Zika syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, ... ...

Abstract	Congenital Zika syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, and dysgenesis of the corpus callosum. Many studies have focused on microcephaly, but it remains unknown how ZIKV infection leads to callosal malformation. To tackle this issue, we infected mouse embryos in utero with a Brazilian ZIKV isolate and found that they were born with a reduction in callosal area and density of callosal neurons. ZIKV infection also causes a density reduction in PH3+ cells, intermediate progenitor cells, and SATB2+ neurons. Moreover, axonal tracing revealed that callosal axons are reduced and misrouted. Also, ZIKV-infected cultures show a reduction in callosal axon length. GFAP labeling showed that an in utero infection compromises glial cells responsible for midline axon guidance. In sum, we showed that ZIKV infection impairs critical steps of corpus callosum formation by disrupting not only neurogenesis, but also axon guidance and growth across the midline.
MeSH term(s)	Pregnancy ; Female ; Humans ; Animals ; Mice ; Zika Virus Infection ; Microcephaly ; Zika Virus ; Corpus Callosum ; Pregnancy Complications, Infectious ; Nervous System Malformations/etiology ; Neurogenesis
Language	English
Publishing date	2023-11-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15122336
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Article ; Online: In vitro susceptibility of eighteen clinical isolates of human monkeypox virus to tecovirimat.

Nunes, Desiree Dos Santos / Higa, Luiza M / Oliveira, Régis Linhares / da Costa, Lendel Correia / Bomfim, Larissa Maciel / Gonçalves, Cássia Cristina Alves / Mariani, Diana / Hruby, Dennis E / Voloch, Carolina Moreira / Castiñeiras, Terezinha Marta Pereira Pinto / Tanuri, Amilcar / Damaso, Clarissa R

Memorias do Instituto Oswaldo Cruz

2023 Volume 118, Page(s) e230056

Abstract: Background: In 2022, an outbreak of mpox that started in European countries spread worldwide through human-to-human transmission. Cases have been mostly mild, but severe clinical presentations have been reported. In these cases, tecovirimat has been the ...

Abstract	Background: In 2022, an outbreak of mpox that started in European countries spread worldwide through human-to-human transmission. Cases have been mostly mild, but severe clinical presentations have been reported. In these cases, tecovirimat has been the drug of choice to treat patients with aggravated disease. Objectives: Here we investigated the tecovirimat susceptibility of 18 clinical isolates of monkeypox virus (MPXV) obtained from different regions of Brazil. Methods: Different concentrations of tecovirimat were added to cell monolayers infected with each MPXV isolate. After 72 hours, cells were fixed and stained for plaque visualization, counting, and measurement. The ortholog of F13L gene from each MPXV isolate was polymerase chain reaction (PCR)-amplified, sequenced, and the predicted protein sequences were analyzed. Findings: The eighteen MPXV isolates generated plaques of different sizes. Although all isolates were highly sensitive to the drug, two showed different response curves and IC50 values. However, the target protein of tecovirimat, F13 (VP37), was 100% conserved in all MPXV isolates and therefore does not explain the difference in sensitivity. Main conclusions: Our results support screening different MPXV isolates for tecovirimat susceptibility as an important tool to better use of the restricted number of tecovirimat doses available in low-income countries to treat patients with mpox.
MeSH term(s)	Humans ; Mpox (monkeypox) ; Monkeypox virus/genetics ; Amino Acid Sequence ; Benzamides
Chemical Substances	Benzamides
Language	English
Publishing date	2023-07-10
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	953293-6
ISSN	1678-8060 ; 0074-0276
ISSN (online)	1678-8060
ISSN	0074-0276
DOI	10.1590/0074-02760230056
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Article ; Online: Co-circulation of vaccinia and monkeypox viruses in rural areas of Brazil: Importance of differential molecular diagnosis.

Luques, Matheus Nobrega / Oliveira, Régis Linhares / Hir, Samuel / Nunes, Desiree Dos Santos / Higa, Luiza M / Mendonça, Ana Flávia / Pereira, Luiz Augusto / Sousa, Fabrício / Castiñeiras, Terezinha Marta Pereira Pinto / Tanuri, Amilcar / Damaso, Clarissa R

Travel medicine and infectious disease

2023 Volume 53, Page(s) 102578

MeSH term(s)	Humans ; Vaccinia/diagnosis ; Vaccinia/epidemiology ; Monkeypox virus/genetics ; Brazil/epidemiology ; Vaccinia virus/genetics ; Diagnosis, Differential
Language	English
Publishing date	2023-04-22
Publishing country	Netherlands
Document type	Letter
ZDB-ID	2170891-5
ISSN	1873-0442 ; 1477-8939
ISSN (online)	1873-0442
ISSN	1477-8939
DOI	10.1016/j.tmaid.2023.102578
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Article ; Online: Assessing the role of Ndel1 oligopeptidase activity in congenital Zika syndrome: Potential predictor of congenital syndrome endophenotype and treatment response.

Christoff, Raissa R / Nani, João V / Lessa, Gabriel / Rabello, Tailene / Rossi, Atila D / Krenn, Veronica / Higa, Luiza M / Tanuri, Amilcar / Garcez, Patricia P / Hayashi, Mirian A F

Journal of neurochemistry

2023 Volume 166, Issue 4, Page(s) 763–776

Abstract: Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum ... ...

Abstract	Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like-1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)-beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN-beta that is able to rescue the ZIKV-induced brain injury.
MeSH term(s)	Animals ; Mice ; Zika Virus Infection/complications ; Zika Virus Infection/congenital ; Zika Virus Infection/pathology ; Microcephaly ; Zika Virus ; Endophenotypes ; Carrier Proteins
Chemical Substances	oligopeptidase (EC 3.4.-) ; Ndel1 protein, mouse ; Carrier Proteins
Language	English
Publishing date	2023-07-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15918
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Article ; Online: Copper regulation disturbance linked to oxidative stress and cell death during Zika virus infection in human astrocytes.

Puig-Pijuan, Teresa / Souza, Leticia R Q / Pedrosa, Carolina da S G / Higa, Luiza M / Monteiro, Fabio Luis / Tanuri, Amilcar / Valverde, Rafael H F / Einicker-Lamas, Marcelo / Rehen, Stevens Kastrup

Journal of cellular biochemistry

2022

Abstract: The Zika virus (ZIKV) caused neurological abnormalities in more than 3500 Brazilian newborns between 2015 and 2020. Data have pointed to oxidative stress in astrocytes as well as to dysregulations in neural cell proliferation and cell cycle as important ... ...

Abstract	The Zika virus (ZIKV) caused neurological abnormalities in more than 3500 Brazilian newborns between 2015 and 2020. Data have pointed to oxidative stress in astrocytes as well as to dysregulations in neural cell proliferation and cell cycle as important events accounting for the cell death and neurological complications observed in Congenital Zika Syndrome. Copper imbalance has been shown to induce similar alterations in other pathologies, and disturbances in copper homeostasis have already been described in viral infections. Here, we investigated copper homeostasis imbalance as a factor that could contribute to the cytotoxic effects of ZIKV infection in astrocytes. Human induced pluripotent stem cell-derived astrocytes were infected with ZIKV; changes in the gene expression of copper homeostasis proteins were analyzed. The effect of the administration of CuCl
Language	English
Publishing date	2022-09-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.30323
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Article ; Online: Mpox outbreak in Rio de Janeiro, Brazil: A translational approach.

Lira, Guilherme S / Ota, Victor A / Melo, Mariana Q S / Castiñeiras, Anna C P / Leitão, Isabela C / Silva, Bianca O / Mariani, Diana / Gonçalves, Cássia C A / Ribeiro, Liane J / Halpern, Marcia / Abreu, Thalita F / Carneiro, Fabiana A / Scheid, Helena T / Souza, Leonardo A V / Rodrigues, Débora G M / Cruz, Nádia V G / Cony, Andrea / Carvalho, Silvia / de Lima, Loyze P O /

Viala, Vincent L / Caldas, Lucio A / de Souza, Wanderley / Higa, Luiza M / Voloch, Carolina M / Ferreira, Orlando C / Damaso, Clarissa R / Galliez, Rafael M / Faffe, Débora S / Tanuri, Amilcar / Castiñeiras, Terezinha M P P

Journal of medical virology

2024 Volume 96, Issue 5, Page(s) e29621

Abstract: Mpox is a zoonotic disease historically reported in Africa. Since 2003, limited outbreaks have occurred outside Africa. In 2022, the global spread of cases with sustained interhuman transmission and unusual disease features raised public health concerns. ...

Abstract	Mpox is a zoonotic disease historically reported in Africa. Since 2003, limited outbreaks have occurred outside Africa. In 2022, the global spread of cases with sustained interhuman transmission and unusual disease features raised public health concerns. We explore the mpox outbreak in Rio de Janeiro (RJ) state, Brazil, in an observational study of mpox-suspected cases from June to December 2022. Data collection relied on a public healthcare notification form. Diagnosis was determined by MPXV-PCR. In 46 confirmed cases, anti-OPXV IgG was determined by ELISA, and seven MPXV genomes were sequenced. A total of 3095 cases were included, 816 (26.3%) with positive MPXV-PCR results. Most positive cases were men in their 30 s and MSM. A total of 285 (34.9%) MPXV-PCR+ patients live with HIV. Eight were coinfected with varicella-zoster virus. Anogenital lesions and adenomegaly were associated with the diagnosis of mpox. Females and individuals under 18 represented 9.4% and 5.4% of all confirmed cases, respectively, showing higher PCR cycle threshold (Ct) values and fewer anogenital lesions compared to adult men. Anti-OPXV IgG was detected in 29/46 (63.0%) patients. All analyzed sequences belonged to clade IIb. In RJ state, mpox presented a diverse clinical picture, represented mainly by mild cases with low complication rates and prominent genital involvement. The incidence in females and children was higher than usually reported. The observation of a bimodal distribution of Ct values, with few positive results, may suggest the need to review the diagnostic criteria in these groups.
MeSH term(s)	Humans ; Brazil/epidemiology ; Male ; Female ; Disease Outbreaks ; Adult ; Young Adult ; Adolescent ; Middle Aged ; Animals ; Zoonoses/epidemiology ; Zoonoses/virology ; Herpesvirus 3, Human/genetics ; Herpesvirus 3, Human/isolation & purification ; Child ; HIV Infections/epidemiology ; HIV Infections/virology ; Antibodies, Viral/blood ; Aged ; Immunoglobulin G/blood
Chemical Substances	Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2024-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Observational Study
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.29621
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Article: From a recombinant key antigen to an accurate, affordable serological test: lessons learnt from COVID-19 for future pandemics

Alvim, Renata G.F. / Lima, Tulio M. / Rodrigues, Danielle A.S. / Marsili, Federico F. / Bozza, Vicente B.T. / Higa, Luiza M. / Monteiro, Fabio L. / Abreu, Daniel P.B. / Leitão, Isabela C. / Carvalho, Renato S. / Galliez, Rafael M. / Castineiras, Terezinha M.P.P. / Travassos, Leonardo H. / Nobrega, Alberto / Tanuri, Amilcar / Ferreira, Orlando C. / Vale, André M. / Castilho, Leda R.

Biochemical engineering journal. 2022 July 09,

2022

Abstract: Serological tests detect antibodies generated by infection or vaccination, and are indispensable tools along different phases of a pandemic, from early monitoring of pathogen spread up to seroepidemiological studies supporting immunization policies. This ...

Abstract	Serological tests detect antibodies generated by infection or vaccination, and are indispensable tools along different phases of a pandemic, from early monitoring of pathogen spread up to seroepidemiological studies supporting immunization policies. This work discusses the development of an accurate and affordable COVID-19 antibody test, from production of a recombinant protein antigen up to test validation and economic analysis. We first developed a cost-effective, scalable technology to produce SARS-COV-2 spike protein and then used this antigen to develop an enzyme-linked immunosorbent assay (ELISA). A receiver operator characteristic (ROC) analysis allowed optimizing the cut-off and confirmed the high accuracy of the test: 98.6% specificity and 95% sensitivity for 11+ days after symptoms onset. We further showed that dried blood spots collected by finger pricking on simple test strips could replace conventional plasma/serum samples. A cost estimate was performed and revealed a final retail price in the range of one US dollar, reflecting the low cost of the ELISA test platform and the elimination of the need for venous blood sampling and refrigerated sample handling in clinical laboratories. The presented workflow can be completed in 4 months from first antigen expression to final test validation. It can be applied to other pathogens and in future pandemics, facilitating reliable and affordable seroepidemiological surveillance also in remote areas and in low-income countries.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; antibodies ; antigens ; blood serum ; cost effectiveness ; cost estimates ; enzyme-linked immunosorbent assay ; market prices ; monitoring ; pandemic ; pathogens ; recombinant proteins ; refrigeration ; vaccination
Language	English
Dates of publication	2022-0709
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	2012139-8
ISSN	1369-703X
ISSN	1369-703X
DOI	10.1016/j.bej.2022.108537
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Article ; Online: A bioluminescent and homogeneous SARS-CoV-2 spike RBD and hACE2 interaction assay for antiviral screening and monitoring patient neutralizing antibody levels.

Alves, Juliano / Engel, Laurie / de Vasconcelos Cabral, Renata / Rodrigues, Eduardo L / de Jesus Ribeiro, Liane / Higa, Luiza M / da Costa Ferreira Júnior, Orlando / Castiñeiras, Terezinha Marta P P / de Carvalho Leitão, Isabela / Tanuri, Amilcar / Goueli, Said A / Zegzouti, Hicham

Scientific reports

2021 Volume 11, Issue 1, Page(s) 18428

Abstract: Here we describe a homogeneous bioluminescent immunoassay based on the interaction between Fc-tagged SARS-CoV-2 Spike RBD and human ACE2, and its detection by secondary antibodies labeled with NanoLuc luciferase fragments LgBit and SmBit. The assay ... ...

Abstract	Here we describe a homogeneous bioluminescent immunoassay based on the interaction between Fc-tagged SARS-CoV-2 Spike RBD and human ACE2, and its detection by secondary antibodies labeled with NanoLuc luciferase fragments LgBit and SmBit. The assay utility for the discovery of novel inhibitors was demonstrated with a panel of anti-RBD antibodies, ACE2-derived miniproteins and soluble ACE2. Studying the effect of RBD mutations on ACE2 binding showed that the N501Y mutation increased RBD apparent affinity toward ACE2 tenfold that resulted in escaping inhibition by some anti-RBD antibodies. In contrast, while E484K mutation did not highly change the binding affinity, it still escaped antibody inhibition likely due to changes in the epitope recognized by the antibody. Also, neutralizing antibodies (NAbs) from COVID-19 positive samples from two distinct regions (USA and Brazil) were successfully detected and the results further suggest the persistence of NAbs for at least 6 months post symptom onset. Finally, sera from vaccinated individuals were tested for NAbs and showed varying neutralizing activity after first and second doses, suggesting the assay can be used to assess immunity of vaccinated populations. Our results demonstrate the broad utility and ease of use of this methodology both for drug discovery and clinical research applications.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/analysis ; Antibodies, Viral/analysis ; Brazil ; COVID-19/immunology ; COVID-19/prevention & control ; Humans ; Luciferases/genetics ; Luciferases/metabolism ; Luminescent Measurements ; Mutation ; Protein Binding ; Protein Domains ; SARS-CoV-2/immunology ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; United States ; Vaccination
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; Luciferases (EC 1.13.12.-) ; nanoluc (EC 1.13.12.-) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-09-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-97330-3
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Article ; Online: Zika Virus Strains and Dengue Virus Induce Distinct Proteomic Changes in Neural Stem Cells and Neurospheres.

Nascimento, Juliana Minardi / Gouvêa-Junqueira, Danielle / Zuccoli, Giuliana S / Pedrosa, Carolina da Silva Gouveia / Brandão-Teles, Caroline / Crunfli, Fernanda / Antunes, André S L M / Cassoli, Juliana S / Karmirian, Karina / Salerno, José Alexandre / de Souza, Gabriela Fabiano / Muraro, Stéfanie Primon / Proenca-Módena, Jose Luiz / Higa, Luiza M / Tanuri, Amilcar / Garcez, Patricia P / Rehen, Stevens K / Martins-de-Souza, Daniel

Molecular neurobiology

2022 Volume 59, Issue 9, Page(s) 5549–5563

Abstract: Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential ...

Abstract	Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential viral molecular targets have not been fully elucidated. Here we explore the proteomic alterations induced by ZIKV by comparing the Brazilian (Br ZIKV) and the African (MR766) viral strains, in addition to comparing them to the molecular responses to the Dengue virus type 2 (DENV). Neural stem cells (NSCs) derived from induced pluripotent stem (iPSCs) were cultured both as monolayers and in suspension (resulting in neurospheres), which were then infected with ZIKV (Br ZIKV or ZIKV MR766) or DENV to assess alterations within neural cells. Large-scale proteomic analyses allowed the comparison not only between viral strains but also regarding the two- and three-dimensional cellular models of neural cells derived from iPSCs, and the effects on their interaction. Altered pathways and biological processes were observed related to cell death, cell cycle dysregulation, and neurogenesis. These results reinforce already published data and provide further information regarding the biological alterations induced by ZIKV and DENV in neural cells.
MeSH term(s)	Dengue Virus ; Humans ; Neural Stem Cells/metabolism ; Proteomics ; Zika Virus ; Zika Virus Infection
Language	English
Publishing date	2022-06-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-02922-3
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