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Phase III+: The University is open for expanded research operations; only authorized personnel will be admitted on campus. More info here.
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Phase III+: The University is open for expanded research operations; only authorized personnel will be admitted on campus. More info here.

Publications search

Found 37003 matches. Displaying 31-40
Goncalves-Carneiro D, Mastrocola E, Lei X, DaSilva J, Chan YF, Bieniasz PD
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Rational attenuation of RNA viruses with zinc finger antiviral protein

NATURE MICROBIOLOGY 2022 OCT; 7(10):1558-+
Attenuation of a virulent virus is a proven approach for generating vaccines but can be unpredictable. For example, synonymous recoding of viral genomes can attenuate replication but sometimes results in pleiotropic effects that confound rational vaccine design. To enable specific, conditional attenuation of viruses, we examined target RNA features that enable zinc finger antiviral protein (ZAP) function. ZAP recognized CpG dinucleotides and targeted CpG-rich RNAs for depletion, but RNA features such as CpG numbers, spacing and surrounding nucleotide composition that enable specific modulation by ZAP were undefined. Using synonymously mutated HIV-1 genomes, we defined several sequence features that govern ZAP sensitivity and enable stable attenuation. We applied rules derived from experiments with HIV-1 to engineer a mutant enterovirus A71 genome whose attenuation was stable and strictly ZAP-dependent, both in cell culture and in mice. The conditionally attenuated enterovirus A71 mutant elicited neutralizing antibodies that were protective against wild-type enterovirus A71 infection and disease in mice. ZAP sensitivity can thus be readily applied for the rational design of conditionally attenuated viral vaccines. Rational design of live-attenuated RNA viruses with potential as vaccines is enabled by identification of sequence rules for zinc finger antiviral protein.
Yang N, Garcia A, Meyer C, Tuschl T, Merghoub T, Wolchok JD, Deng L
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Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

NPJ VACCINES 2022 OCT 19; 7(1):? Article 120
Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2.
Singh PK, Chen ZL, Horn K, Norris EH
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Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms

RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS 2022 OCT; 6(7):? Article e12815
Background The contact system is initiated by factor (F) XII activation and the assembly of high molecular weight kininogen (HK) with either FXI or prekallikrein (PK) on a negatively charged surface. Overactivation of this system contributes to thrombosis and inflammation in numerous diseases. To develop effective therapeutics for contact system disorders, a detailed understanding of this pathway is needed. Methods We performed coagulation assays in normal human plasma and various factor-deficient plasmas. To evaluate how HK-mediated PK and FXI activation contributes to coagulation, we used an anti-HK antibody to block access to domain 6 of HK, the region required for efficient activation of PK and FXI. Results FXI's binding to HK and its subsequent activation by activated FXII contributes to coagulation. We found that the 3E8 anti-HK antibody can inhibit the binding of FXI or PK to HK, delaying clot formation in human plasma. Our data show that in the absence of FXI, however, PK can substitute for FXI in this process. Addition of activated FXI (FXIa) or activated PK (PKa) abolished the inhibitory effect of 3E8. Moreover, the requirement of HK in intrinsic coagulation can be largely bypassed by adding FXIa. Like FXIa, exogenous PKa shortened the clotting time in HK-deficient plasma, which was not due to feedback activation of FXII. Conclusions This study improves our understanding of HK-mediated coagulation and provides an explanation for the absence of bleeding in HK-deficient individuals. 3E8 specifically prevented HK-mediated FXI activation; therefore, it could be used to prevent contact activation-mediated thrombosis without altering hemostasis.
Gauhar Z, Tejwani L, Abdullah U, Saeed S, Shafique S, Badshah M, Choi J, Dong WL, Nelson-Williams C, Lifton RP, Lim J, Raja GK
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A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family

CELLS 2022 OCT; 11(19):? Article 3090
Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.
Yaron TM, Heaton BE, Levy TM, Johnson JL, Jordan TX, Cohen BM, Kerelsky A, Lin TY, Liberatore KM, Bulaon DK, Nest SJV, Koundouros N, Kastenhuber ER, Mercadante MN, Shobana-Ganesh K, He L, Schwartz RE, Chen SB, Weinstein H, Elemento O, Piskounova E, Nilsson-Payant BE, Lee GA, Trimarco JD, Burke KN, Hamele CE, Chaparian RR, Harding AT, Tata A, Zhu XY, Tata PR, Smith CM, Possemato AP, Tkachev SL, Hornbeck PV, Beausoleil SA, Anand SK, Aguet F, Getz G, Davidson AD, Heesom K, Kavanagh-Williamson M, Matthews DA, tenOever BR, Cantley LC, Blenis J, Heaton NS
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Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication

SCIENCE SIGNALING 2022 OCT 25; 15(757):? Article eabm0808
Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Al-though vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral rep-lication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphor-ylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.
Zhou PC
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Protein vaccine NVX-CoV2373 elicits functional T cell immunity

JOURNAL OF CLINICAL INVESTIGATION 2022 OCT 3; 132(19):? Article e163614
The SARS-CoV-2 vaccine NVX-CoV2373 is a protein-based vaccine that might circumvent the difficulties in distributing mRNA vaccines to regions with limited access to cold-chain and refrigeration. However, the NVX-CoV2373-induced T cell and antibody responses remain poorly understood. In this issue of the JCI, Moderbacher et al. characterized SARS-CoV-2-specific CD4(+) and CD8(+) T cell responses elicited by one or two doses of NVX-CoV2373 in individuals enrolled in a phase I/IIa trial. Substantially increased spike-specific CD4(+) and T follicular helper cells were found after the first or second vaccine dose, with some individuals developing a modest spike-specific CD8(+) T cell response. Correlation analysis revealed an association between spike-specific CD4(+) T cells and neutralizing antibody titers. Notably, preexisting T cell immunity showed negligible effects on NVX-CoV2373-induced T cell responses. These findings indicate that the protein-based vaccine NVX-CoV2373 induces robust T cell immunity capable of recognizing SARS-CoV-2 antigens and supporting humoral immune responses.
Obado SO, Rout MP, Field MC
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Sending the message: specialized RNA export mechanisms in trypanosomes

TRENDS IN PARASITOLOGY 2022 OCT; 38(10):854-867
Export of RNA from the nucleus is essential for all eukaryotic cells and has emerged as a major step in the control of gene expression. mRNA molecules are required to complete a complex series of processing events and pass a quality control system to protect the cytoplasm from the translation of aberrant proteins. Many of these events are highly conserved across eukaryotes, reflecting their ancient origin, but significant deviation from a canonical pathway as described from animals and fungi has emerged in the trypanosomatids. With significant implications for the mechanisms that control gene expression and hence differentiation, responses to altered environments and fitness as a parasite, these deviations may also reveal additional, previously unsuspected, mRNA export pathways.
Unda SR, Marciano S, Milner TA, Marongiu R
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State-of-the-art review of the clinical research on menopause and hormone replacement therapy association with Parkinson's disease: What meta-analysis studies cannot tell us

FRONTIERS IN AGING NEUROSCIENCE 2022 OCT 20; 14(?):? Article 971007
The menopause is a midlife endocrinological process that greatly affects women's central nervous system functions. Over the last 2 decades numerous clinical studies have addressed the influence of ovarian hormone decline on neurological disorders like Parkinson's disease and Alzheimer's disease. However, the findings in support of a role for age at menopause, type of menopause and hormone replacement therapy on Parkinson's disease onset and its core features show inconsistencies due to the heterogeneity in the study design. Here, we provide a unified overview of the clinical literature on the influence of menopause and ovarian hormones on Parkinson's disease. We highlight the possible sources of conflicting evidence and gather considerations for future observational clinical studies that aim to explore the neurological impact of menopause-related features in Parkinson's disease.
Yoney A, Bai L, Brivanlou AH, Siggia ED
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Mechanisms underlying WNT-mediated priming of human embryonic stem cells

DEVELOPMENT 2022 OCT; 149(20):? Article dev200335
Embryogenesis is guided by a limited set of signaling pathways dynamically expressed in different places. How a context-dependent signaling response is generated has been a central question of developmental biology, which can now be addressed with in vitro models of human embryos that are derived from embryonic stem cells (hESCs). Our previous work demonstrated that during early stages of hESC differentiation, cells chronicle signaling hierarchy. Only cells that have been exposed (primed) by WNT signaling can respond to subsequent activin exposure and differentiate to mesendodermal (ME) fates. Here, we show that WNT priming does not alter SMAD2 binding nor its chromatin opening but, instead, acts by inducing the expression of the SMAD2 co-factor EOMES. Expression of EOMES is sufficient to replace WNT upstream of activin-mediated ME differentiation, thus unveiling the mechanistic basis for priming and cellular memory in early development.
Renert-Yuval Y, da Rosa JC, Garcet S, Pavel AB, Bares J, Chima M, Hawkes JE, Gilleaudeau P, Sullivan-Whalen M, Singer GK, Krueger JG, Guttman-Yassky E
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Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes

BRITISH JOURNAL OF DERMATOLOGY 2022 OCT; 187(4):539-547
Background Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes. Objectives Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials. Methods In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes. Results While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'. Conclusions AASIS is better than AA-QLI to assess patient-reported outcomes. SALT <= 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with <= 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials.