UMass Chan Faculty and Staff Research and Publicationshttp://hdl.handle.net/20.500.14038/182024-03-28T17:47:26Z2024-03-28T17:47:26ZModeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1Duan, YeLi, LiPanzade, Ganesh PrabhakarPiton, AmélieZinovyeva, AnnaAmbros, Victor R.http://hdl.handle.net/20.500.14038/532252024-03-27T03:38:06Z2024-02-27T00:00:00ZModeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1
Duan, Ye; Li, Li; Panzade, Ganesh Prabhakar; Piton, Amélie; Zinovyeva, Anna; Ambros, Victor R.
MicroRNAs (miRNA) associate with Argonaute (AGO) proteins and repress gene expression by base pairing to sequences in the 3' untranslated regions of target genes. De novo coding variants in the human AGO genes AGO1 and AGO2 cause neurodevelopmental disorders (NDD) with intellectual disability, referred to as Argonaute syndromes. Most of the altered amino acids are conserved between the miRNA-associated AGO in Homo sapiens and Caenorhabditis elegans, suggesting that the human mutations could disrupt conserved functions in miRNA biogenesis or activity. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homologous gene, alg-1. These alg-1 NDD mutations cause phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC (miRNA silencing complex) formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic, causing developmental and molecular phenotypes stronger than those of alg-1 null mutants, likely by sequestrating functional miRISC components into non-functional complexes. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or messenger RNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental AGO functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.
2024-02-27T00:00:00ZPersistent False Positive Covid-19 Rapid Antigen TestsHerbert, CarlyMcManus, David DSoni, Apurvhttp://hdl.handle.net/20.500.14038/532242024-03-26T15:24:27Z2024-02-22T00:00:00ZPersistent False Positive Covid-19 Rapid Antigen Tests
Herbert, Carly; McManus, David D; Soni, Apurv
Rapid antigen tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective tools for the diagnosis of acute infection, particularly when used serially. The percentage of rapid antigen tests with false positive results is reported to be less than 1%. However, we have observed persons who repeatedly test positive with rapid antigen tests despite concurrent negative molecular tests; this infrequent phenomenon occurs predominantly among women and persons with autoimmune disorders.
2024-02-22T00:00:00ZHarmonizing the Generation and Pre-publication Stewardship of FAIR Image data [preprint]Bialy, NikkiAlber, FrankAndrews, BrendaAngelo, MichaelBeliveau, BrianBintu, LacramioaraBoettiger, AlistairBoehm, UlrikeBrown, Claire MMaina, Mahmoud BukarChambers, James JCimini, Beth AEliceiri, KevinErrington, RachelFaklaris, OrestisGaudreault, NathalieGermain, Ronald NGoscinski, WojtekGrunwald, DavidHalter, MichaelHanein, DoritHickey, John WLacoste, JudithLaude, AlexLundberg, EmmaMa, JianMalacrida, LeonelMoore, JoshNelson, GlynNeumann, Elizabeth KathleenNitschke, RolandOnami, ShuichiPimentel, Jaime APlant, Anne LRadtke, Andrea JSabata, BikashSchapiro, DenisSchöneberg, JohannesSpraggins, Jeffrey MSudar, DamirAdrien Maria Vierdag, Wouter-MichielVolkmann, NielsWählby, CarolinaWang, Siyuan StevenYaniv, ZivStrambio-De-Castillia, Caterinahttp://hdl.handle.net/20.500.14038/531702024-03-12T03:36:49Z2024-02-08T00:00:00ZHarmonizing the Generation and Pre-publication Stewardship of FAIR Image data [preprint]
Bialy, Nikki; Alber, Frank; Andrews, Brenda; Angelo, Michael; Beliveau, Brian; Bintu, Lacramioara; Boettiger, Alistair; Boehm, Ulrike; Brown, Claire M; Maina, Mahmoud Bukar; Chambers, James J; Cimini, Beth A; Eliceiri, Kevin; Errington, Rachel; Faklaris, Orestis; Gaudreault, Nathalie; Germain, Ronald N; Goscinski, Wojtek; Grunwald, David; Halter, Michael; Hanein, Dorit; Hickey, John W; Lacoste, Judith; Laude, Alex; Lundberg, Emma; Ma, Jian; Malacrida, Leonel; Moore, Josh; Nelson, Glyn; Neumann, Elizabeth Kathleen; Nitschke, Roland; Onami, Shuichi; Pimentel, Jaime A; Plant, Anne L; Radtke, Andrea J; Sabata, Bikash; Schapiro, Denis; Schöneberg, Johannes; Spraggins, Jeffrey M; Sudar, Damir; Adrien Maria Vierdag, Wouter-Michiel; Volkmann, Niels; Wählby, Carolina; Wang, Siyuan Steven; Yaniv, Ziv; Strambio-De-Castillia, Caterina
Together with the molecular knowledge of genes and proteins, biological images promise to significantly enhance the scientific understanding of complex cellular systems and to advance predictive and personalized therapeutic products for human health. For this potential to be realized, quality-assured image data must be shared among labs at a global scale to be compared, pooled, and reanalyzed, thus unleashing untold potential beyond the original purpose for which the data was generated. There are two broad sets of requirements to enable image data sharing in the life sciences. One set of requirements is articulated in the companion White Paper entitled "Enabling Global Image Data Sharing in the Life Sciences," which is published in parallel and addresses the need to build the cyberinfrastructure for sharing the digital array data (arXiv:2401.13023 [q-bio.OT], https://doi.org/10.48550/arXiv.2401.13023). In this White Paper, we detail a broad set of requirements, which involves collecting, managing, presenting, and propagating contextual information essential to assess the quality, understand the content, interpret the scientific implications, and reuse image data in the context of the experimental details. We start by providing an overview of the main lessons learned to date through international community activities, which have recently made considerable progress toward generating community standard practices for imaging Quality Control (QC) and metadata. We then provide a clear set of recommendations for amplifying this work. The driving goal is to address remaining challenges, and democratize access to common practices and tools for a spectrum of biomedical researchers, regardless of their expertise, access to resources, and geographical location.
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
2024-02-08T00:00:00ZMicrobiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine [preprint]Kellogg, Tasia DCeglia, SimonaMortzfeld, Benedikt MZeamer, Abigail LFoley, Sage EWard, Doyle VBhattarai, Shakti KMcCormick, Beth AReboldi, AndreaBucci, Vannihttp://hdl.handle.net/20.500.14038/531712024-03-12T03:36:56Z2024-01-31T00:00:00ZMicrobiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine [preprint]
Kellogg, Tasia D; Ceglia, Simona; Mortzfeld, Benedikt M; Zeamer, Abigail L; Foley, Sage E; Ward, Doyle V; Bhattarai, Shakti K; McCormick, Beth A; Reboldi, Andrea; Bucci, Vanni
Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile-induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3+/-, and nullified in the tuft cell knockout mouse, Pou2f3-/-, confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
2024-01-31T00:00:00ZAssociation of spatial proximity to fixed-site syringe services programs with HCV serostatus and injection equipment sharing practices among people who inject drugs in rural New England, United StatesRomo, EricStopka, Thomas JJesdale, Bill MWang, BoMazor, Kathleen MFriedmann, Peter Dhttp://hdl.handle.net/20.500.14038/530662024-02-16T03:13:52Z2024-01-28T00:00:00ZAssociation of spatial proximity to fixed-site syringe services programs with HCV serostatus and injection equipment sharing practices among people who inject drugs in rural New England, United States
Romo, Eric; Stopka, Thomas J; Jesdale, Bill M; Wang, Bo; Mazor, Kathleen M; Friedmann, Peter D
Background: Hepatitis C virus (HCV) disproportionately affects rural communities, where health services are geographically dispersed. It remains unknown whether proximity to a syringe services program (SSP) is associated with HCV infection among rural people who inject drugs (PWID).
Methods: Data are from a cross-sectional sample of adults who reported injecting drugs in the past 30 days recruited from rural counties in New Hampshire, Vermont, and Massachusetts (2018-2019). We calculated the road network distance between each participant's address and the nearest fixed-site SSP, categorized as ≤ 1 mile, 1-3 miles, 3-10 miles, and > 10 miles. Staff performed HCV antibody tests and a survey assessed past 30-day injection equipment sharing practices: borrowing used syringes, borrowing other used injection equipment, and backloading. Mixed effects modified Poisson regression estimated prevalence ratios (aPR) and 95% confidence intervals (95% CI). Analyses were also stratified by means of transportation.
Results: Among 330 PWID, 25% lived ≤ 1 mile of the nearest SSP, 17% lived 1-3 miles of an SSP, 12% lived 3-10 miles of an SSP, and 46% lived > 10 miles from an SSP. In multivariable models, compared to PWID who lived within 1 mile of an SSP, those who lived 3 to 10 miles away had a higher prevalence of HCV seropositivity (aPR: 1.25, 95% CI 1.06-1.46), borrowing other used injection equipment (aPR: 1.23, 95% CI 1.04-1.46), and backloading (aPR: 1.48, 95% CI 1.17-1.88). Similar results were observed for PWID living > 10 miles from an SSP: aPR [HCV]: 1.19, 95% CI 1.01-1.40; aPR [borrowing other used equipment]:1.45, 95% CI 1.29-1.63; and aPR [backloading]: 1.59, 95% CI 1.13-2.24. Associations between living 1 to 3 miles of an SSP and each outcome did not reach statistical significance. When stratified by means of transportation, associations between distance to SSP and each outcome (except borrowing other used injection equipment) were only observed among PWID who traveled by other means (versus traveled by automobile).
Conclusions: Among PWID in rural New England, living farther from a fixed-site SSP was associated with a higher prevalence of HCV seropositivity, borrowing other used injection equipment, and backloading, reinforcing the need to increase SSP accessibility in rural areas. Means of transportation may modify this relationship.
2024-01-28T00:00:00ZInvestigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencingLevine, Zoë CSene, AitaMkandawire, WinnieDeme, Awa BNdiaye, TollaSy, MouhamadGaye, AmyDiedhiou, YounoussMbaye, Amadou MNdiaye, Ibrahima MGomis, JulesNdiop, MédouneSene, DoudouFaye Paye, MarietouMacInnis, Bronwyn LSchaffner, Stephen FPark, Daniel JBadiane, Aida SColubri, AndresNdiaye, MouhamadouSy, NgayoSabeti, Pardis CNdiaye, DaoudaSiddle, Katherine Jhttp://hdl.handle.net/20.500.14038/530992024-03-06T03:46:46Z2024-01-25T00:00:00ZInvestigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing
Levine, Zoë C; Sene, Aita; Mkandawire, Winnie; Deme, Awa B; Ndiaye, Tolla; Sy, Mouhamad; Gaye, Amy; Diedhiou, Younouss; Mbaye, Amadou M; Ndiaye, Ibrahima M; Gomis, Jules; Ndiop, Médoune; Sene, Doudou; Faye Paye, Marietou; MacInnis, Bronwyn L; Schaffner, Stephen F; Park, Daniel J; Badiane, Aida S; Colubri, Andres; Ndiaye, Mouhamadou; Sy, Ngayo; Sabeti, Pardis C; Ndiaye, Daouda; Siddle, Katherine J
The worldwide decline in malaria incidence is revealing the extensive burden of non-malarial febrile illness (NMFI), which remains poorly understood and difficult to diagnose. To characterize NMFI in Senegal, we collected venous blood and clinical metadata in a cross-sectional study of febrile patients and healthy controls in a low malaria burden area. Using 16S and untargeted sequencing, we detected viral, bacterial, or eukaryotic pathogens in 23% (38/163) of NMFI cases. Bacteria were the most common, with relapsing fever Borrelia and spotted fever Rickettsia found in 15.5% and 3.8% of cases, respectively. Four viral pathogens were found in a total of 7 febrile cases (3.5%). Sequencing also detected undiagnosed Plasmodium, including one putative P. ovale infection. We developed a logistic regression model that can distinguish Borrelia from NMFIs with similar presentation based on symptoms and vital signs (F1 score: 0.823). These results highlight the challenge and importance of improved diagnostics, especially for Borrelia, to support diagnosis and surveillance.
2024-01-25T00:00:00ZEffect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C [preprint]Preiss, AlexanderBhatia, AbhishekZang, ChengxiAragon, Leyna VBaratta, John MBaskaran, MonikaBlancero, FrankBrannock, M DanielChew, Robert FDíaz, IvánFitzgerald, MeganKelly, Elizabeth PZhou, AndreaWeiner, Mark GCarton, Thomas WWang, FeiKaushal, RainuChute, Christopher GHaendel, MelissaMoffitt, RichardPfaff, Emilyhttp://hdl.handle.net/20.500.14038/531122024-03-08T05:43:44Z2024-01-22T00:00:00ZEffect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C [preprint]
Preiss, Alexander; Bhatia, Abhishek; Zang, Chengxi; Aragon, Leyna V; Baratta, John M; Baskaran, Monika; Blancero, Frank; Brannock, M Daniel; Chew, Robert F; Díaz, Iván; Fitzgerald, Megan; Kelly, Elizabeth P; Zhou, Andrea; Weiner, Mark G; Carton, Thomas W; Wang, Fei; Kaushal, Rainu; Chute, Christopher G; Haendel, Melissa; Moffitt, Richard; Pfaff, Emily
Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC. We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,461 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. Our primary outcome measure was a PASC computable phenotype. Secondary outcomes were the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.99, 95% confidence interval [CI] 0.96-1.01). However, its effect varied across the cognitive (RR = 0.85, 95% CI 0.79-0.90), fatigue (RR = 0.93, 95% CI 0.89-0.96), and respiratory (RR = 0.99, 95% CI 0.95-1.02) symptom clusters, suggesting that Paxlovid treatment may help prevent post-acute cognitive and fatigue symptoms more than others.
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
2024-01-22T00:00:00ZComparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positiveHarrold, Leslie RWittstock, KeithKelly, SheilaHan, XueZhuo, JoeSchrader, AmyMiddaugh, NicoleMoore, Page CKhaychuk, Vadimhttp://hdl.handle.net/20.500.14038/530362024-02-15T04:18:58Z2024-01-19T00:00:00ZComparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive
Harrold, Leslie R; Wittstock, Keith; Kelly, Sheila; Han, Xue; Zhuo, Joe; Schrader, Amy; Middaugh, Nicole; Moore, Page C; Khaychuk, Vadim
Background: The HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive.
Methods: Abatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used.
Results: In the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045).
Conclusion: In this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort..
2024-01-19T00:00:00ZDog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging ProjectNam, YunbiWhite, MichelleKarlsson, Elinor KCreevy, Kate EPromislow, Daniel E LMcClelland, Robyn Lhttp://hdl.handle.net/20.500.14038/531032024-03-08T05:47:07Z2024-01-17T00:00:00ZDog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging Project
Nam, Yunbi; White, Michelle; Karlsson, Elinor K; Creevy, Kate E; Promislow, Daniel E L; McClelland, Robyn L
Age in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size patterns are complex. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. In this study we seek to quantify how the pattern of disease history varies across the spectrum of dog size, dog age, and their interaction. Utilizing owner-reported data on disease history from a substantial number of companion dogs enrolled in the Dog Aging Project, we investigate how body size, as measured by weight, associates with the lifetime prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between dog size and the lifetime prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, dog size was negatively associated with lifetime prevalence of ocular, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by size. We also found that the association between age and lifetime disease prevalence varied by dog size for many conditions including ocular, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred vs. mixed-breed status, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories and suggest potential avenues for further examination.
2024-01-17T00:00:00ZDo organisms need an impact factor? Citations of key biological resources including model organisms reveal usage patterns and impact [preprint]Piekniewska, AgataAnderson, NathanRoelandse, MartijnLloyd, K C KentKorf, IanVoss, S Randalde Castro, GiovanniMagnani, Diogo MVarga, ZoltanJames-Zorn, ChristinaHorb, MarkoGrethe, Jeffery SBandrowski, Anitahttp://hdl.handle.net/20.500.14038/531722024-03-12T03:34:06Z2024-01-16T00:00:00ZDo organisms need an impact factor? Citations of key biological resources including model organisms reveal usage patterns and impact [preprint]
Piekniewska, Agata; Anderson, Nathan; Roelandse, Martijn; Lloyd, K C Kent; Korf, Ian; Voss, S Randal; de Castro, Giovanni; Magnani, Diogo M; Varga, Zoltan; James-Zorn, Christina; Horb, Marko; Grethe, Jeffery S; Bandrowski, Anita
Research resources like transgenic animals and antibodies are the workhorses of biomedicine, enabling investigators to relatively easily study specific disease conditions. As key biological resources, transgenic animals and antibodies are often validated, maintained, and distributed from university based stock centers. As these centers heavily rely largely on grant funding, it is critical that they are cited by investigators so that usage can be tracked. However, unlike systems for tracking the impact of papers, the conventions and systems for tracking key resource usage and impact lag behind. Previous studies have shown that about 50% of the resources are not findable, making the studies they are supporting irreproducible, but also makes tracking resources difficult. The RRID project is filling this gap by working with journals and resource providers to improve citation practices and to track the usage of these key resources. Here, we reviewed 10 years of citation practices for five university based stock centers, characterizing each reference into two broad categories: findable (authors could use the RRID, stock number, or full name) and not findable (authors could use a nickname or a common name that is not unique to the resource). The data revealed that when stock centers asked their communities to cite resources by RRID, in addition to helping stock centers more easily track resource usage by increasing the number of RRID papers, authors shifted from citing resources predominantly by nickname (~50% of the time) to citing them by one of the findable categories (~85%) in a matter of several years. In the case of one stock center, the MMRRC, the improvement in findability is also associated with improvements in the adherence to NIH rigor criteria, as determined by a significant increase in the Rigor and Transparency Index for studies using MMRRC mice. From this data, it was not possible to determine whether outreach to authors or changes to stock center websites drove better citation practices, but findability of research resources and rigor adherence was improved.
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
2024-01-16T00:00:00Z