bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioenvironmental Adversity and Adolescent Psychotic Experiences: Exploring Potential Mechanisms in a UK Longitudinal Cohort
Authors: Newbury Joanne B , Arseneault Louise , Moffitt Terrie E , Odgers Candice L , Howe Laura D , Bakolis Ioannis , Reuben Aaron , Danese Andrea , Sugden Karen , Williams Benjamin , Rasmussen Line J H , Trotta Antonella , Ambler Antony P , Fisher Helen L
Published: March 2023

Background and Hypothesis

Children exposed to socioenvironmental adversities (eg, urbanicity, pollution, neighborhood deprivation, crime, and family disadvantage) are more likely to subsequently develop subclinical psychotic experiences during adolescence (eg, hearing voices, paranoia). However, the pathways through which this occurs have not been previously investigated. We hypothesized that cognitive ability and inflammation would partly explain this association.

Study Design

Data were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994–1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences.

Study Results

Higher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses.

Conclusions

Cognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.
Hypothyroidism‐associated immunosuppression involves induction of galectin‐1‐producing regulatory T cells
Authors: Valli Eduardo , Dalotto‐Moreno Tomás , Sterle Helena A. , Méndez‐Huergo Santiago P. , Paulazo María A. , García Silvia I. , Pirola Carlos J. , Klecha Alicia J. , Rabinovich Gabriel A. , Cremaschi Graciela A.
Published: March 2023

Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamic–pituitary–thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barely understood. Here, we investigated the mechanisms underlying hypothyroid‐related immunosuppression by examining the regulatory role of components of the HPT axis. We first analyzed lymphocyte activity in mice overexpressing the TRH gene (Tg‐Trh). T cells from Tg‐Trh showed increased proliferation than wild‐type (WT) euthyroid mice in response to polyclonal activation. The release of Th1 pro‐inflammatory cytokines was also increased in Tg‐Trh and TSH levels correlated with T‐cell proliferation. To gain further mechanistic insights into hypothyroidism‐related immunosuppression, we evaluated T‐cell subpopulations in lymphoid tissues of hypothyroid and control mice. No differences were observed in CD3/CD19 or CD4/CD8 ratios between these strains. However, the frequency of regulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg‐Trh mice. Accordingly, in vitro Tregs differentiation was more pronounced in naïve T cells isolated from hypothyroid mice. Since Tregs overexpress galectin‐1 (Gal‐1) and mice lacking this lectin (Lgals1−/−) show reduced Treg function, we investigated the involvement of this immunoregulatory lectin in the control of Tregs in settings of hypothyroidism. Increased T lymphocyte reactivity and reduced frequency of Tregs were found in hypothyroid Lgals1−/− mice when compared to hypothyroid WT animals. This effect was rescued by the addition of recombinant Gal‐1. Finally, increased expression of Gal‐1 was found in Tregs purified from hypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase in the frequency and activity of Gal‐1‐expressing Tregs underlies immunosuppression associated with hypothyroid conditions, with critical implications in immunopathology, metabolic disorders, and cancer.
A single‐cell gene expression atlas of human follicular aspirates: Identification of leukocyte subpopulations and their paracrine factors
Authors: Choi Yohan , Jeon Hayce , Brännström Mats , Akin James W. , Curry Thomas E. , Jo Misung
Published: March 2023

Leukocytes are in situ regulators critical for ovarian function. However, little is known about leukocyte subpopulations and their interaction with follicular cells in ovulatory follicles, especially in humans. Single‐cell RNA sequencing (scRNA‐seq) was performed using follicular aspirates obtained from four IVF patients and identified 13 cell groups: one granulosa cell group, one thecal cell group, 10 subsets of leukocytes, and one group of RBC/platelet. RNA velocity analyses on five granulosa cell populations predicted developmental dynamics denoting two projections of differentiation states. The cell type‐specific transcriptomic profiling analyses revealed the presence of a diverse array of leukocyte‐derived factors that can directly impact granulosa cell function by activating their receptors (e.g., cytokines and secretory ligands) and are involved in tissue remodeling (e.g., MMPs, ADAMs, ADAMTSs, and TIMPs) and angiogenesis (e.g., VEGFs, PGF, FGF, IGF, and THBS1) in ovulatory follicles. Consistent with the findings from the scRNA‐seq data, the leukocyte‐specific expression of CD68, IL1B, and MMP9 was verified in follicle tissues collected before and at defined hours after hCG administration from regularly cycling women. Collectively, this study demonstrates that this data can be used as an invaluable resource for identifying important leukocyte‐derived factors that promote follicular cell function, thereby facilitating ovulation and luteinization in women.
ZNF32 prevents the activation of cancer‐associated fibroblasts through negative regulation of TGFB1 transcription in breast cancer
Authors: Li Qin , Yuan Hang , Zhao Gang , Zhang Jie , Li Siqi , Gong Di , Feng Tianyu , Kou Qiming , Wang Qijing , Wang Guanru , Li Shan , Li Kai , Lin Ping
Published: March 2023

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer‐related deaths in women worldwide. Cancer‐associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF‐related markers (FSP1, α‐SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency‐mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the −1968/−1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF‐β stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.
FGF1 ameliorates obesity‐associated hepatic steatosis by reversing IGFBP2 hypermethylation
Authors: Wang Jie , Zhang Feng , Yang Weiwei , Gao Dandan , Yang Linglong , Yu Chenhua , Chen Chengshui , Li Xiaokun , Zhang Jin‐San
Published: March 2023

Obesity is a major contributing factor for metabolic‐associated fatty liver disease (MAFLD). Fibroblast growth factor (FGF) 1 is the first paracrine FGF family member identified to exhibit promising metabolic regulatory properties capable of conferring glucose‐lowering and insulin‐sensitizing effect. This study explores the role and molecular underpinnings of FGF1 in obesity‐associated hepatic steatosis. In a mouse high‐fat diet (HFD)‐induced MAFLD model, chronic treatment with recombinant FGF1(rFGF1) was found to effectively reduce the severity of insulin resistance, hyperlipidemia, and inflammation. FGF1 treatment decreased lipid accumulation in the mouse liver and palmitic acid‐treated AML12 cells. These effects were associated with decreased mature form SREBF1 expression and its target genes FASN and SCD1. Interestingly, we uncovered that rFGF1 significantly induced IGFBP2 expression at both mRNA and protein levels in HFD‐fed mouse livers and cultured hepatocytes treated with palmitic acid. Adeno‐associated virus‐mediated IGFBP2 suppression significantly diminished the therapeutic benefit of rFGF1 on MAFLD‐associated phenotypes, indicating that IGFBP2 plays a crucial role in the FGF1‐mediated reduction of hepatic steatosis. Further analysis revealed that rFGF1 treatment reduces the recruitment of DNA methyltransferase 3 alpha to the IGFBP2 genomic locus, leading to decreased IGFBP2 gene methylation and increased mRNA and protein expression. Collectively, our findings reveal FGF1 modulation of lipid metabolism via epigenetic regulation of IGFBP2 expression, and unravel the therapeutic potential of the FGF1‐IGFBP2 axis in metabolic diseases associated with obesity.
SAMHD1restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase‐positive cells
Authors: D'Aronco Giulia , Ferraro Paola , Sassano Valentina , Dagostino Claudia , Biancotto Melissa , Palumbo Elisa , Presot Ettore , Russo Antonella , Bianchi Vera , Rampazzo Chiara
Published: March 2023

SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain‐containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular dNTP pools, which support genome integrity. In SAMHD1 deficient fibroblasts isolated from Aicardi‐Goutières Syndrome (AGS) patients, all four DNA precursors are increased and markedly imbalanced with the largest effect on dGTP, a key player in the modulation of telomerase processivity. Here, we present data showing that SAMHD1, by restricting the dGTP pool, contributes to telomere maintenance in hTERT‐immortalized human fibroblasts from AGS patients as well as in telomerase positive cancer cell lines. Only in cells expressing telomerase, the lack of SAMHD1 causes excessive lengthening of telomeres and telomere fragility, whereas primary fibroblasts lacking both SAMHD1 and telomerase enter normally into senescence. Telomere lengthening observed in SAMHD1 deficient but telomerase proficient cells is a gradual process, in accordance with the intrinsic property of telomerase of adding only a few tens of nucleotides for each cycle. Therefore, only a prolonged exposure to high dGTP content causes telomere over‐elongation. hTERT‐immortalized AGS fibroblasts display also high fragility of chromosome ends, a marker of telomere replication stress. These results not only demonstrate the functional importance of dGTP cellular level but also reveal the critical role played by SAMHD1 in restraining telomerase processivity and safeguarding telomere stability.
Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review
Authors: Cai Luyao , Chen Guanjie , Yang Haichen , Bai Yuanhan
Published: March 2023

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen’s d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine–fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.
Increased Influenza Severity in Children in the Wake of SARS-CoV-2
Authors: Hoy Gregory , Maier Hannah E. , Kuan Guillermina , Sánchez Nery , López Roger , Meyers Alyssa , Plazaola Miguel , Ojeda Sergio , Balmaseda Angel , Gordon Aubree
Published: March 2023

The SARS-CoV-2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few pre-pandemic exposures. We compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two pre-pandemic seasons and found an increased frequency of severe influenza in 2022.
Fronto-central resting-state 15-29Hz transient beta events change with therapeutic transcranial magnetic stimulation for posttraumatic stress disorder and major depressive disorder
Authors: Morris Alexander T. , Temereanca Simona , Zandvakili Amin , Thorpe Ryan , Sliva Danielle D. , Greenberg Benjamin D. , Carpenter Linda L. , Philip Noah S. , Jones Stephanie R.
Published: March 2023

Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD) and shows promise for posttraumatic stress disorder (PTSD), yet effectiveness varies. Electroencephalography (EEG) can identify rTMS-associated brain changes. EEG oscillations are often examined using averaging approaches that mask finer time-scale dynamics. Recent advances show some brain oscillations emerge as transient increases in power, a phenomenon termed “Spectral Events,” and that event characteristics correspond with cognitive functions. We applied Spectral Event analyses to identify potential EEG biomarkers of effective rTMS treatment. Resting 8-electrode EEG was collected from 23 patients with MDD and PTSD before and after 5Hz rTMS targeting the left dorsolateral prefrontal cortex. Using an open-source toolbox (https://github.com/jonescompneurolab/SpectralEvents), we quantified event features and tested for treatment associated changes. Spectral Events in delta/theta (1-6 Hz), alpha (7-14 Hz), and beta (15-29 Hz) bands occurred in all patients. rTMS-induced improvement in comorbid MDD PTSD were associated with pre-to post-treatment changes in fronto-central electrode beta event features, including frontal beta event frequency spans and durations, and central beta event maxima power. Furthermore, frontal pre-treatment beta event duration correlated negatively with MDD symptom improvement. Beta events may provide new biomarkers of clinical response and advance the understanding of rTMS.
An investigation of the association between characteristics of local crisis care systems and service use in a national survey
Authors: Rojas-García Antonio , Dalton-Locke Christian , Rains Luke Sheridan , Dare Ceri , Ginestet Cedric , Foye Una , Kelly Kathleen , Landau Sabine , Lynch Chris , McCrone Paul , Nairi Shilpa , Newbigging Karen , Nyikavaranda Patrick , Osborn David , Persaud Karen , Sevdalis Nick , Stefan Martin , Stuart Ruth , Simpson Alan , Johnson Sonia , Lloyd-Evans Brynmor
Published: March 2023

Background

In England, a range of mental health crisis care models and approaches to organising crisis care systems have been implemented, but characteristics associated with their effectiveness are poorly understood.

Aims

To i) develop a typology of catchment area mental health crisis care systems and ii) investigate how crisis care service models and system characteristics relate to psychiatric hospital admissions and detentions.

Methods

Data about crisis systems were obtained from a 2019 English national survey. Latent class analyses were conducted to identify discernible typologies, and mixed effects negative binomial regression models were fitted to explore associations between crisis care models and admissions and detention rates, obtained from nationally-reported data.

Results

No clear typology of catchment area crisis care systems emerged. Regression models suggested that provision of a crisis telephone service within the local crisis system was associated to a 11.6% lower admissions rate and a 15.3% lower detention rate. Provision of a crisis café was associated with a 7.8% lower rate of admissions. The provision of a crisis assessment team separate from the crisis resolution and home treatment service was associated with a 12.8% higher rate of admissions.

Conclusions

The configuration of crisis care systems varies considerably in England, but we could notderive a typology which convincingly categorised crisis care systems. Our results suggest that a crisis phone line and a crisis café may be associated with lower rates of admission, but crisis assessment teams, separate from home treatment teams, may not be associate to reductions in hospital admission and detentions.
Predicting COVID-19 pandemic waves with biologically and behaviorally informed universal differential equations
Authors: Kuwahara Bruce , Bauch Chris T.
Published: March 2023

In the early stages of the COVID-19 pandemic, it became clear that pandemic waves and population responses were locked in a mutual feedback loop. The initial lull following strict interventions in the first wave often led to a second wave, as restrictions were relaxed. We test the ability of new hybrid machine learning techniques, namely universal differential equations (UDEs) with learning biases, to make predictions in a such a dynamic behavior-disease setting. We develop a UDE model for COVID-19 and test it both with and without learning biases describing simple assumptions about disease transmission and population response. Our results show that UDEs, particularly when supplied with learning biases, are capable of learning coupled behavior-disease dynamics and predicting second waves in a variety of populations. The model predicts a second wave of infections 55% of the time across all populations, having been trained only on the first wave. The predicted second wave is larger than the first. Without learning biases, model predictions are hampered: the unbiased model predicts a second wave only 25% of the time, typically smaller than the first. The biased model consistently predicts the expected increase in the transmission rate with rising mobility, whereas the unbiased model predicts a decrease in mobility as often as a continued increase. The biased model also achieves better accuracy on its training data thanks to fewer and less severely divergent trajectories. These results indicate that biologically informed machine learning can generate qualitatively correct mid to long-term predictions of COVID-19 pandemic waves.

Significance statement

Universal differential equations are a relatively new modelling technique where neural networks use data to learn unknown components of a dynamical system. We demonstrate for the first time that this technique is able to extract valuable information from data on a coupled behaviour-disease system. Our model was able to learn the interplay between COVID-19 infections and time spent travelling to retail and recreation locations in order to predict a second wave of cases, having been trained only on the first wave. We also demonstrate that adding additional terms to the universal differential equation’s loss function that penalize implausible solutions improves training time and leads to improved predictions.
Increased vaccine sensitivity of an emerging SARS-CoV-2 variant
Authors: Lewnard Joseph A. , Hong Vennis , Kim Jeniffer S. , Shaw Sally F. , Lewin Bruno , Takhar Harpreet , Lipsitch Marc , Tartof Sara Y.
Published: March 2023

Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with improvements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and ≥5 COVID-19 vaccine doses were 10% (95% confidence interval: 1-18%), 11% (3-19%), 13% (3-21%), and 25% (15-34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30-87%] and 48% [7-71%], respectively, for recipients of ≥4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11-24%) and 40% (19-65%) higher adjusted odds of having experienced 1 and ≥2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses.
Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in Long COVID
Authors: Al-Hakeim Hussein Kadhem , Abed Anwar Khairi , Moustafa Shatha Rouf , Almulla Abbas F , Maes Michael
Published: March 2023

Background

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN) and quinolinic acid. The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

Methods

In the present study, we measured serum tryptophan (TRY), TRYCATs, insulin resistance (using the HOMA2-IR index), C-reactive protein (CRP), physiosomatic, depression and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection.

Results

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome. Three Long COVID biomarkers (CRP, KYN/TRY, IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, IR (Long COVID), and PBT and SpO2 (acute COVID-19).

Conclusion

The physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID and lowered plasma tryptophan and increased kynurenine may contribute to these effects.
Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary
Authors: Cavazzoni Andrea , Salamon Irene , Fumarola Claudia , Gallerani Giulia , Laprovitera Noemi , Gelsomino Francesco , Riefolo Mattia , Rihawi Karim , Porcellini Elisa , Rossi Tania , Mazzeschi Martina , Naddeo Maria , Serravalle Salvatore , Broseghini Elisabetta , Agostinis Federico , Deas Olivier , Roncarati Roberta , Durante Giorgio , Lauriola Mattia , Garajova Ingrid , Calin George A. , Bonafè Massimiliano , D’Errico Antonia , Petronini Pier Giorgio , Cairo Stefano , Ardizzoni Andrea , Sales Gabriele , Ferracin Manuela
Published: March 2023

Patients with cancer of unknown primary (CUP) carry the burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96), and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and FISH analysis identified FGFR2 gene amplification in both models, in the form of homogenously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ-398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, bothin vitroandin vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.
mRNA aggregates harness danger response for potent cancer immunotherapy
Authors: Mendez-Gomez Hector R. , DeVries Anna , Castillo Paul , Stover Brian D. , Qdaisat Sadeem , Von Roemeling Christina , Ogando-Rivas Elizabeth , Weidert Frances , McGuiness James , Zhang Dingpeng , Chung Michael C. , Li Derek , Zhang Chong , Marconi Christiano , Campaneria Yodarlynis , Chardon-Robles Jonathan , Grippin Adam , Karachi Aida , Thomas Nagheme , Huang Jianping , Milner Rowan , Sahay Bikash , Sawyer W. Gregory , Ligon John A. , Silver Natalie , Simon Eugenio , Cleaver Brian , Wynne Kristine , Hodik Marcia , Molinaro Anette , Guan Juan , Kellish Patrick , Doty Andria , Lee Ji-Hyun , Carrera-Justiz Sheila , Rahman Maryam , Gatica Sebastian , Mueller Sabine , Prados Michael , Ghiaseddin Ashley , Mitchell Duane A. , Sayour Elias J.
Published: March 2023

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of ‘onion-like’ multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.
Reduced effectiveness of repeat influenza vaccination: distinguishing among within-season waning, recent clinical infection, and subclinical infection
Authors: Bi Qifang , Dickerman Barbra A. , Nguyen Huong Q. , Martin Emily T. , Gaglani Manjusha , Wernli Karen J. , Balasubramani G.K. , Flannery Brendan , Lipsitch Marc , Cobey Sarah ,   the US Flu Vaccine Effectiveness Network Investigators
Published: March 2023

1

Abstract1

Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A(H3N2) (OR=1.11, 95%CI:1.02-1.21) but not for influenza B or A(H1N1). We found that clinical infection influenced individuals’ decision to vaccinate in the following season while protecting against clinical infection of the same (sub)type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on VE.

Summary of main points: Two potential factors, timing of vaccination and clinical infection history, cannot fully explain the increased influenza infection risk in repeat vaccinees compared with non-repeat vaccinees. Subclinical infection in the previous season may explain the effect.
Modelling the impact of hybrid immunity on future COVID-19 epidemic waves
Authors: Le Thao P. , Abell Isobel , Conway Eamon , Campbell Patricia T. , Hogan Alexandra B. , Lydeamore Michael J. , McVernon Jodie , Mueller Ivo , Walker Camelia R. , Baker Christopher M.
Published: March 2023

Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization (WHO) Western Pacific Region (WPR). We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.
Dengue virus infected patients can generate false positives in the ‘gold standard’Leptospiraspp. microscopic agglutination test (MAT), immunofluorescence assays (IFAs), and immunoblot assays due to cross-reactive IgG and/or IgM antibodies against their outer surface membrane proteins
Authors: Romero-Vivas Claudia M. , Cuello-Pérez Margarett , Falconar Andrew K.
Published: March 2023

There are overlapping world distributions of the mosquito-borne dengue viruses (DENVs) and water-borne bacterial disease leptospirosis which cause large numbers of human infections and fatalities. As such, early differential diagnosis is required for appropriate early leptospirosis antibiotic therapy or DENV patient supportive care, but co-infections have also been reported. From 200 paired (S1 and S2) serum samples collected from suspected DENV infected patients, 70 (35%) were confirmed as ‘on-going’ infections by demonstrating>4-fold S1 to S2 sample increased anti-DENV IgG and/or IgM ELISA titers. Of those, 8.57% (6/70) also displayed>4-fold increased S1 to S2 sample titers in the ‘gold standard’Leptospiraspp. microscopic agglutination test (MAT) and paraformaldehyde (cell-membrane-impermeable fixative) treated leptospires in immunofluorescence assays (IFAs) due to cross-reactions with 68-72 and 38-42 KDa outer surface membrane antigens present on allLeptospiraspp. serovars tested. While DENV-1, -2 or -3 serotypes were isolated from their S1 sera: a)Leptospiraspp. could not be isolated from them, b) their S1 sera were all PCR-negative using aLeptospiraspp.-specific gene target, and c) their S2 sera were all negative using a commercial anti-Leptospiraspp. IgM ELISA. As such, we believe this is the first report of DENVs causing false positive reactions in the ‘gold standard’Leptospiraspp. MAT, IFAs, and immunoblot assays and which needs further assessments using patients’ samples which were possibly falsely reported as ‘DENV-Leptospiraspp. co-infections’ in other studies, and to identify these 68-72 and 38-42 KDaLeptospiraspp. outer surface membrane antigens by proteomic analyses.
Improved performance of nucleic acid-based assays for genetically diverse norovirus surveillance
Authors: Oh Chamteut , Zhou Aijia , O’Brien Kate , Schmidt Arthur R , Shisler Joanna L. , Schmidt Arthur R , Keefer Laura , Brown William M. , Nguyen Thanh H.
Published: March 2023

Nucleic acid-based assays, such as polymerase chain reaction (PCR), that amplify and detect organism-specific genome sequences are a standard method for infectious disease surveillance. However, challenges arise for virus surveillance because of their genetic diversity. Here, we calculated the variability of nucleotides within the genomes of ten human viral speciesin silicoand found that endemic viruses exhibit a high percentage of variable nucleotides (e.g., 51.4% for norovirus GII). This genetic diversity led to variable probability of detection of PCR assays (the proportion of viral sequences that contain the assay’s target sequences divided by the total number of viral sequences). We then experimentally confirmed that the probability of the target sequence detection is indicative of the number of mismatches between PCR assays and norovirus genomes. Next, we developed a degenerate PCR assay that detects 97% of known norovirus GII genome sequences and recognized norovirus in eight clinical samples. In contrast, previously developed assays with 31% and 16% probability of detection had 1.1 and 2.5 mismatches on average, respectively, which negatively impacted RNA quantification. Additionally, the two PCR assays with lower probability of detection also resulted in false negatives for wastewater-based epidemiology. Our findings suggest that the probability of detection serves as a simple metric for evaluating nucleic acid-based assays for genetically diverse virus surveillance.

Importance

Nucleic acid-based assays, such as polymerase chain reaction (PCR), that amplify and detect organism-specific genome sequences are a standard method for infectious disease surveillance. However, challenges arise for virus surveillance because of the rapid evolution and genetic variation of viruses. The study analyzed clinical and wastewater samples using multiple PCR assays and found significant performance variation among the PCR assays for genetically diverse norovirus surveillance. This finding suggests that some PCR assays may miss detecting certain virus strains, leading to a compromise in detection sensitivity. To address this issue, we propose a metric called the probability of detection, which can be simply calculatedin silicousing a code developed in this study, to evaluate nucleic acid-based assays for genetically diverse virus surveillance. This new approach can help improve the sensitivity and accuracy of virus detection, which is crucial for effective infectious disease surveillance and control.
Comparison of Capillary Blood Self-Collection using the Tasso-SST Device with Venous Phlebotomy for anti-SARS-CoV-2 Antibody Measurement
Authors: King Elise R. , Garrett Haley E. , Abernathy Haley , Cassidy Caitlin A. , Cabell Cameron R. , Shook-Sa Bonnie E. , Juliano Jonathan J. , Boyce Ross M. , Aiello Allison E. , Ciccone Emily J.
Published: March 2023

Measuring seroprevalence over time is a valuable epidemiological tool for improving our understanding of COVID-19 immunity. Due to the large number of collections required for population surveillance as well as concerns about potential infection risk to the collectors, self-collection approaches are being increasingly pursued. To advance this methodology, we collected paired venous and capillary blood samples by routine phlebotomy and Tasso-SST device respectively from 26 participants and measured total immunoglobulin (Ig) and IgG antibodies to the SARS-CoV-2 receptor binding domain (RBD) by enzyme-linked immunosorbent assay (ELISA) on both specimens. Qualitatively, no discrepancies were noted in binary results between Tasso and venipuncture-derived plasma. Furthermore, in vaccinated participants, correlation between Tasso and venous total Ig and IgG specific antibody quantitative levels was high (Total Ig: ρ = 0.72, 95% CI (0.39- 0.90); IgG: ρ = 0.85, 95% CI (0.54, 0.96)). Our results support the use of Tasso at-home collection devices for antibody testing.
The genetic relationships between brain structure and schizophrenia
Authors: Stauffer Eva-Maria , Bethlehem Richard A.I. , Dorfschmidt Lena , Won Hyejung , Warrier Varun , Bullmore Edward T.
Published: March 2023

Recent studies suggest shared genetic effects on both schizophrenia and brain structure, but it has been challenging to specify which genes mediate this pleiotropic association. We accessed genome-wide association data on schizophrenia (N=69,369 cases; 236,642 controls), and on three magnetic resonance imaging (MRI) metrics (surface area, cortical thickness, neurite density index) measured at 180 cortical areas (N=36,843). Using Hi-C-coupled MAGMA, we identified 61 genes that were significantly associated with both schizophrenia and one or more MRI metrics. Whole genome analysis demonstrated significant genetic covariation between schizophrenia and area or thickness of most cortical regions. Genetic similarity between cortical areas was strongly coupled to covariance of their MRI metrics, and genetic covariation between schizophrenia and cortical regional phenotypes was greatest in the hubs of the corresponding structural covariance network. Three genomic regions, on chromosomes 3p21, 17q21 and 11p11, were enriched for neurodevelopmental processes and consistently implicated in these pleiotropic associations between schizophrenia and cortical network organization.
Rare Variants in Pharmacogenes Influence Clozapine Metabolism in Individuals with Schizophrenia
Authors: Kappel Djenifer B. , Rees Elliott , Fenner Eilidh , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T.R. , Pardiñas Antonio F.
Published: March 2023

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and the occurrence of adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. Our main aim is to investigate whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤1%) in gene sets broadly related to drug pharmacokinetics and lower clozapine (β= -0.054, SE= 0.019, P-value= 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. Gene-based analysis identified rare variants inCYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (β= 0.324, SE= 0.124, P= 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations. These results also converge with common variant evidence, particularly in relation toCYP1A2, suggesting the need for further evaluations of the pharmacogenomic makeup of this gene. Overall, our results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles.
Importation of Alpha and Delta variants during the SARS-CoV-2 epidemic in Switzerland: phylogenetic analysis and intervention scenarios
Authors: Reichmuth Martina L , Hodcroft Emma B , Althaus Christian L
Published: March 2023

The SARS-CoV-2 pandemic has led to the emergence of various variants of concern (VoCs) that are associated with increased transmissibility, immune evasion, or differences in disease severity. The emergence of VoCs fueled interest in understanding the potential impact of travel restrictions and surveillance strategies to prevent or delay the early spread of VoCs. We performed phylogenetic analyses and mathematical modeling to study the importation and spread of the VoCs Alpha and Delta in Switzerland in 2020 and 2021. Using a phylogenetic approach, we estimated 383-1,038 imports of Alpha and 455-1,347 imports of Delta into Switzerland. We then used the results from the phylogenetic analysis to parameterize a dynamic transmission that accurately described the subsequent spread of Alpha and Delta. We modeled different counterfactual intervention scenarios to quantify the potential impact of border closures and surveillance of travelers on the spread of Alpha and Delta. We found that implementing border closures after the announcement of VoCs would have been of limited impact to mitigate the spread of VoCs. In contrast, increased surveillance of travelers could prove to be an effective measure for delaying the spread of VoCs in situations where their severity remains unclear. Our study shows how phylogenetic analysis in combination with dynamic transmission models can be used to estimate the number of imported SARS-CoV-2 variants and the potential impact of different intervention scenarios to inform the public health response during the pandemic.
Genetic insights into the age-specific biological mechanisms governing human ovarian ageing
Authors: Ojavee Sven E. , Darrous Liza , Patxot Marion , Läll Kristi , Fischer Krista , Mägi Reedik , Kutalik Zoltan , Robinson Matthew R.
Published: March 2023

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modelling framework, which determines the time-dependency of DNA variant-age-at-onset associations, without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the sign of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages, and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age-dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modelling of large-scale biobank data.
High prevalence and dependence of centrosome clustering in mesenchymal tumors and leukemia
Authors: Marín Nuria Moreno , Marteil Gaelle , Fresmann Nora C. , de Almeida Bernardo P. , Dores Katharina , Fragoso Rita , Vaz Joana Cardoso , Leal Jose B. Pereira , Taborda Barata João Pedro , Godinho Susana A , Barbosa-Morais Nuno L , Bettencourt-Dias Monica
Published: March 2023

The presence of supernumerary centrosomes is a hallmark of cancer and is frequently observed in aggressive tumors. Cancer cells with centrosome amplification achieve pseudo-bipolar spindles through specific coping mechanisms in order to survive. However, their distribution and prevalence in cancer remain largely unknown. Here, using the NCI60 panel of cancer cell lines, we show that the presence of coping strategies correlates with centrosome amplification, with the clustering of extra-centrosomes within the two spindle poles being the most widespread mechanism. Moreover, we report an association between centrosome clustering ability and the epithelial-to-mesenchymal transition (EMT) and observe that the induction of mesenchymal characteristics in breast cancer cells with centrosome amplification promotes clustering. Furthermore, we unveil hematological malignancies, which lack epithelial characteristics, as the most proficient in centrosome clustering. Finally, we show that acute lymphoblastic leukemia is particularly sensitive to targeting clustering through inhibition of the spindle assembly checkpoint. Our study reveals how centrosome clustering and EMT collaborate to promote carcinogenesis, suggesting new possibilities to treat tumors with low epithelial characteristics, in particular leukemias.