bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-perception of mental health, COVID-19 and associated sociodemographic-contextual factors in Latin American
Authors: Roa Pablo , Rosas Guillermo , Niño Cruz Gloria Isabel , Moreno López Sergio Mauricio , Mejía Grueso Juliana , Aguirre-Loaiza Haney , Alarcón Aguilar Javiera , Reis Rodrigo , Hino Adriano Akira , López Fernando , Salvo Deborah , Ramírez Varela Andrea
Published: December 2023

Objective

This study aimed to estimate the prevalence of alterations in the self-perception of mental health (SpMH) during the COVID-19 pandemic and their associated factors in four Latin American countries. Methods: A cross-sectional study of data collected from adults in 2021 through the McDonnell Collaborative COVID-19 Response Survey. The sample was composed by 8125 people from Brazil, Colombia, Mexico, and Chile. A generalized linear model (GLM) for a binary outcome variable with a logistic link and fixed country effects was used. Results: There were 2336 (28.75%) people who considered having suffered alterations in SpMH. The unemployed [OR: 1.40 (95% CI: 1.24–1.58)], those with bad/regular quality of life [OR: 5.03 (95% CI: 4.01-6.31)], and those with high socioeconomic status (SES) [OR: 1.66 (95% CI: 1.41–1.96)] had a higher risk of SpMH alterations than those with full-time employment, excellent quality, and low SES status. According to the fixed-effects model, Brazilians living in the country during the pandemic, who disagreed with their government’s decisions [OR: 2.05 (95%CI: 1.74–2.42)] and lacked trust in their government [OR: 2.10 (95%CI: 1.74–2.42)] had a higher risk of having SpMH alterations. Conclusion: Nearly 30.0% of respondents indicated that the COVID-19 pandemic altered their SpMH. This outcome was associated with political, sociodemographic, and health risk factors. These findings should help policymakers develop post-pandemic community interventions.
Association Between Person-Centered Care Quality and Advance Care Planning Participation in Patients Undergoing Hemodialysis: A Multicenter Cross-Sectional Study
Authors: Kanakubo Yusuke , Kurita Noriaki , Ukai Mamiko , Aita Tetsuro , Inanaga Ryohei , Kawaji Atsuro , Toishi Takumi , Matsunami Masatoshi , Munakata Yu , Suzuki Tomo , Okada Tadao
Published: December 2023

Rationale & Objective

Person-centered care (PCC), which incorporates patients’ preferences and values not only for medical care but also for their life, in decision making has been proposed for promoting advance care planning (ACP) among patients with kidney failure.

However, how variations in PCC affect ACP participation remain unclear. Therefore, we examined variations in PCC across facilities and examined the association between PCC and ACP participation.

Study Design

Multicenter cross-sectional study.

Setting & Participants

Japanese adults receiving outpatient hemodialysis at six dialysis centers.

Exposures

PCC was measured using the 13-item Japanese version of the Primary Care Assessment Tool-short form.

Outcome

ACP participation as defined by discussion with the attending physician or written documentation or notes regarding treatment preferences.

Analytical Approach

A general linear model was used to examine the correlates of the quality of PCC. Modified Poisson regression models were used to examine the associations of ACP participation.

Results

A total of 453 individuals were analyzed; 26.3% participated in ACP. Compared to respondents with no usual source of care (USC), higher PCC was associated with greater ACP participation in a dose-response manner (vs. no USC, adjusted prevalence ratios for the first to fourth quartiles: 1.36, 2.31, 2.64, and 3.10, respectively). Among the PCC sub-domains, first contact, longitudinality, comprehensiveness (services provided), and community orientation were particularly associated with ACP participation. There was a maximum of 12.0 points of facility variation in the quality of PCC.

Limitations

Possible reverse causation and unmeasured confounders.

Conclusions

High PCC quality was associated with ACP participation. The substantial disparity in PCC between facilities provides an opportunity to revisit the quality improvement in PCC.
Negative Clinical Outcomes Between Silver Diamine Fluoride, Sedation, and General Anesthesia Treatment for Children with Early Childhood Caries: A Cohort Study
Authors: Okuji David , Dinh Yen , McClure Tony , Lee Myeonggyun
Published: December 2023

Purpose

This study compared the wait-time for treatment completion and pre- and post-treatment outcomes of treating early childhood caries with silver diamine fluoride, sedation, and general anesthesia.

Methods

This retrospective study examined children with early childhood caries treated with either silver diamine fluoride, sedation, or general anesthesia at federally qualified health centers. Demographics, wait-time for treatment completion, and pre- and post-treatment clinical outcomes were compared with analysis of variance for continuous variables and the Chi-square test for categorical variables. This study was reviewed and approved by Southcentral Foundation Research Review.

Results

The outcomes between the silver diamine fluoride, sedation, and general anesthesia groups were respectively: 1) average wait-times to complete treatment at 49.6, 62.5, and 116.3 days, 2) mean number of pre-treatment visits at 1.08, 1.25, and 1.61, 3) mean number of post-treatment visits at 1.41, 1.29, and 1.45.

Multiple negative outcomes were identified when the sedation and general anesthesia groups were compared with the silver diamine fluoride reference group for 1) pre-treatment visits with un-planned visits (for general anesthesia only), pain, intra-oral swelling, and prescriptions for pain and antibiotic medications (general anesthesia only) and 2) post-treatment visits with new carious lesions on permanent molars, new carious lesions on primary teeth (sedation only), intra-oral swelling (sedation only only), broken restorations, displaced restorations, and pulpal therapy (sedation only).

Conclusions

Silver diamine fluoride provides timely and effective caries management with lower wait-time for treatment completion, clinical outcomes consistent with minimally invasive treatment, and mitigation for the risk of negative pre- and post-operative clinical outcomes compared to treatment under sedation or general anesthesia.
Using Natural Language Processing as a Scalable Mental Status Evaluation Technique
Authors: Wagner Margot , Jagayat Jasleen , Kumar Anchan , Shirazi Amir , Alavi Nazanin , Omrani Mohsen
Published: December 2023

Mental health is in a state of crisis with demand for mental health services significantly surpassing available care. As such, building scalable and objective measurement tools for mental health evaluation is of primary concern. Given the usage of spoken language in diagnostics and treatment, it stands out as potential methodology. Here a model is built for mental health status evaluation using natural language processing. Specifically, a RoBERTa-based model is fine-tuned on text from psychotherapy sessions to predict mental health status with prediction accuracy on par with clinical evaluations at 74%.
Prognostic impact of atrial function in cardiac sarcoidosis using two-dimensional speckle-tracking echocardiography
Authors: Nishihara Takahiro , Takaya Yoichi , Nakayama Rie , Yoshida Yu , Toh Norihisa , Nakamura Kazufumi , Yuasa Shinsuke
Published: December 2023

Aims

Although ventricular dysfunction is associated with adverse outcomes in cardiac sarcoidosis (CS), the potential role of atrial function is unknown. The aim of this study was to assess the effect of atrial function on clinical outcomes in patients with CS.

Methods

We retrospectively enrolled 96 patients with CS. Left atrial (LA) and right atrial (RA) function was calculated as LA global longitudinal strain (LAGLS) and RA global longitudinal strain (RAGLS), respectively, using two-dimensional speckle-tracking echocardiography. Major adverse cardiac event (MACE) was a composite of cardiac death, fatal ventricular arrhythmia events, and hospitalization for heart failure.

Results

During a median follow-up of 6.0 years, 37 patients had MACE. LAGLS and RAGLS were lower in patients with MACE than in those without MACE. Kaplan-Meier curves showed that patients with atrial dysfunction with LAGLS of ≤ 19.6% or RAGLS of ≤ 22.3% had a higher rate of MACE than those without atrial dysfunction (log-rank test, p = 0.01 for both comparisons). The presence of LAGLS of ≤ 19.6% or RAGLS of ≤ 22.3% was significantly associated with MACE in a model that included age, sex, and New York Heart Association class (hazard ratio: 2.19, 95% confidence interval: 1.06–4.55, p = 0.04; hazard ratio: 2.27, 95% confidence interval: 1.07–4.85, p = 0.03, respectively).

Conclusions

Atrial dysfunction represented by LAGLS and RAGLS is associated with adverse outcomes in patients with CS. Our findings suggest a potential role of atrial function for predicting the prognosis in CS.
Understanding Cardiac Events in Breast Cancer (UCARE) - Pilot Cardio-Oncology Assessment and Surveillance Pathway for Breast Cancer Patients
Authors: Cronin Michael , Lowery Aoife , McInerney Veronica , Wijns William , Kerin Michael , Keane Maccon , Blazkova Silvie , Martin Michael , Soliman Osama
Published: December 2023

In Ireland, over 3,000 patients are diagnosed with breast cancer annually, and 1 in 9 Irish women will be diagnosed with breast cancer in their lifetime. There is evidence that female breast cancer survivors are more likely to die of cardiovascular disease than their age-matched counterparts. This protocol describes a prospective, single arm, pilot feasibility study implementing a dedicated Cardio-Oncology assessment and surveillance pathway for patients receiving multimodal breast cancer treatment. It incorporates novel biomarker and radiomic surveillance and monitoring approaches for cancer-therapy related cardiac dysfunction into routine care for breast cancer patients undergoing adjuvant systemic chemotherapy.
Effect of mechanical stretching stimulation on maturation of human iPS cell-derived cardiomyocytes co-cultured with human gingival fibroblasts
Authors: Wang Mengxue , Idei Harumi , Wang Chen , Liang Yin , Liu Yun , Matsuda Yusuke , Takahashi Ken , Kamioka Hiroshi , Naruse Keiji
Published: December 2023

In the realm of regenerative medicine, despite the various techniques available for inducing the differentiation of induced pluripotent stem (iPS) cells into cardiomyocytes, there remains a need to enhance the efficiency of this induction process. This study aimed to improve the differentiation efficiency of iPS-derived cardiomyocytes (iPS-CMs) by incorporating mechanical stretching. Human iPS cells were co-cultured with human gingival fibroblasts (HGF) on a polydimethylsiloxane (PDMS) stretch chamber, where mechanical stretching stimulation was applied during the induction of cardiomyocyte differentiation. The maturation of iPS-CMs was assessed using qRT-PCR, immunofluorescence staining, transmission electron microscopy, and contractility comparisons. Results indicated significantly elevated gene expression levels of cardiomyocyte markers (cTnT) and the mesodermal marker (Nkx2.5) in the stretch group compared to the control group. Fluorescent immunocytochemical staining revealed the presence of cardiac marker proteins (cTnT and HCN4) in both groups, with higher protein expression in the stretch group. Additionally, sarcomere length in the stretch group was notably larger than in the control group. A significant increase in the contractility of iPS-CMs was observed in the stretch group. These findings demonstrate that mechanical stretching stimulation enhances the maturity and differentiation efficiency of iPS-CMs co-cultured with fibroblasts.
Rescue of Impaired Blood-Brain Barrier in Tuberous Sclerosis Complex Patient Derived Neurovascular Unit
Authors: Brown Jacquelyn A. , Faley Shannon L. , Judge Monika , Ward Patricia , Ihrie Rebecca A. , Carson Robert , Armstrong Laura , Sahin Mustafa , Wikswo John P. , Ess Kevin C. , Neely M. Diana
Published: December 2023

Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either theTSC1orTSC2gene. Dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). We generated disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. Using these microphysiological systems, we demonstrate that the BBB generated fromTSC2heterozygous mutant cells shows increased permeability which can be rescued by wild type astrocytes and with treatment with rapamycin, an mTOR kinase inhibitor. Our results further demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of the cell lineages contributing to TSC pathogenesis.
A cognitive map for value-guided choice in ventromedial prefrontal cortex
Authors: Veselic Sebastijan , Muller Timothy H. , Gutierrez Elena , Behrens Timothy E. J. , Hunt Laurence T. , Butler James L. , Kennerley Steven W.
Published: December 2023

The prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency – occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples – a key neural signature of planning and flexible behaviour – in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex.
H7 influenza A viruses bind sialyl-LewisX, a potential intermediate receptor between species
Authors: Spruit Cindy M. , Palme Diana I. , Li Tiehai , Ríos Carrasco María , García Alba Gabarroca , Sweet Igor R. , Kuryshko Maryna , Maliepaard Joshua C. L. , Reiding Karli R. , Scheibner David , Boons Geert-Jan , Abdelwhab Elsayed M. , de Vries Robert P.
Published: December 2023

Influenza A viruses (IAVs) can overcome species barriers by adaptation of the receptor binding site of the hemagglutinin (HA). To initiate infection, HAs bind to glycan receptors with terminal sialic acids, which are eitherN-acetylneuraminic acid (NeuAc) orN-glycolylneuraminic acid (NeuGc), the latter is mainly found in horses and pigs but not in birds and humans. We investigated the influence of previously identified equine NeuGc-adapting mutations (S128T, I130V, A135E, T189A, and K193R) in avian H7 IAVsin vitroandin vivo.We observed that these mutations negatively affected viral replication in chicken cells, but not in duck cells, and positively affected replication in horse cells.In vivo, the mutations reduced virus virulence and mortality in chickens. Ducks excreted high viral loads for a longer time than chickens, although they appeared clinically healthy. To elucidate why chickens and ducks were infected by these viruses despite the absence of NeuGc, we re-evaluated the receptor binding of H7 HAs using glycan microarray and flow cytometry studies. This revealed that mutated avian H7 HAs also bound to α2,3-linked NeuAc and sialyl-LewisX, which have an additional fucose moiety in their terminal epitope, explaining why infection of ducks and chickens was possible. Interestingly, the α2,3-linked NeuAc and sialyl-LewisX epitopes were only bound when presented on tri-antennaryN-glycans, emphasizing the importance of investigating the fine receptor specificities of IAVs. In conclusion, the binding of NeuGc-adapted H7 IAV to sialyl-LewisX enables viral replication and shedding by chickens and ducks, potentially facilitating interspecies transmission of equine-adapted H7 IAVs. (249 words)

Importance

Influenza A viruses cause millions of deaths and illness in birds and mammals each year. The viral surface protein hemagglutinin initiates infection by binding to host cell terminal sialic acids. Hemagglutinin adaptations affect the binding affinity to these sialic acids and therefore the potential host species targeted. While avian and human IAVs tend to bindN-acetylneuraminic acid (a form of sialic acid), equine H7 viruses prefer binding toN-glycolylneuraminic acid (NeuGc). To better understand the function of NeuGc-specific adaptations in hemagglutinin and to elucidate interspecies transmission potential NeuGc-adapted viruses, we evaluated the effects of NeuGc-specific mutations in avian H7 viruses in chickens and ducks, important economic hosts and reservoir birds, respectively. We also examined the impact on viral replication and found a binding affinity to sialyl-LewisX, another terminal epitope. These findings are important as they contribute to the understanding of the role of sialyl-LewisX in avian influenza infection. (148 words)
Acidity-induced dysfunction of CD8+T cells is characterized by impaired IL-2 responsiveness and perturbations to mTORC1 signaling and c-Myc levels
Authors: Vuillefroy de Silly Romain , Pericou Laetitia , Seijo Bili , Crespo Isaac , Coukos George , Irving Melita
Published: December 2023

CD8+T cells play a critical role in cancer control but a range of barriers in the tumor microenvironment, including low pH, can impair their function. Here, we demonstrate that acidity dampens T-cell expansion mainly due to impaired IL-2 responsiveness, blunts cytokine secretion upon re-activation, and lowers the cytolytic capacity of CD8+T cells expressing weak affinity TCR. We further reveal and dissect defects in both mTORC1 activity and c-Myc accumulation at low pH, the latter of which is largely due to proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate and aspartate as well as elevated proline were noted, with no apparent impact on mTORC1 or c-Myc. Overall, low pH disrupts diverse intracellular signaling pathways as well as nutrient uptake/processing by T cells and we conclude that unless intracellular pH can be restored, multiple interventions will be required to overcome acidity-induced dysfunction.
Genome organization in double-stranded DNA viruses observed by cryoET
Authors: Chen Muyuan , Sahoo Bibekananda , Mou Zongjun , Song Xiyong , Tsai Tiffany , Dai Xinghong
Published: December 2023

Double-stranded DNA (dsDNA) viruses package their genetic material into protein cages with diameters usually a few hundred times smaller than the length of their genome. Compressing the relatively stiff and highly negatively charged dsDNA into a small volume is energetically costly and mechanistically enigmatic. Multiple models of dsDNA packaging have been proposed based on various experimental evidence and simulation methods, but direct observation of any viral genome organization is lacking. Here, using cryoET and an improved data processing scheme that utilizes information from the encaging protein shell, we present 3D views of dsDNA genome inside individual viral particles at resolution that densities of neighboring DNA duplexes are readily separable. These cryoET observations reveal a “rod-and-coil” fold of the dsDNA that is conserved among herpes simplex virus type 1 (HSV-1) with a spherical capsid, bacteriophage T4 with a prolate capsid, and bacteriophage T7 with a proteinaceous core inside the capsid. Finally, inspired by the genome arrangement in partially packaged T4 particles, we propose a mechanism for the genome packaging process in dsDNA viruses.
High-energy demand and nutrient exhaustion in MTCH2 knockout cells
Authors: Chourasia Sabita , Petucci Christopher , Wang Hu , Han Xianlin , Sivan Ehud , Brandis Alexander , Mehlman Tevie , Malitsky Sergey , Itkin Maxim , Rotkopf Ron , Regev Limor , Zaltsman Yehudit , Gross Atan
Published: December 2023

Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection from diet-induced obesity. We now show using temporal metabolomics that MTCH2 deletion results in a high ATP demand, an oxidized environment, a high lipid/amino acid/carbohydrate metabolism, and in the decrease of many metabolites. Lipidomics analyses show a strategic adaptive decrease in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, all the metabolic changes in the MTCH2 knockout cells were rescued by MTCH2 re-expression. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion inhibits adipocyte differentiation, an energy consuming reductive biosynthetic process. In summary, loss of MTCH2 results in an increase in energy demand that triggers a catabolic and oxidizing environment, which fails to fuel the anabolic processes during adipocyte differentiation.
Osteopontin in colitis-associated carcinoma
Authors: Manna Subhakankha , Sehn Maximilian , Cardoso da Silva Danielle , Wiese Jakob J. , Heldt Claudia , Plumbom Izabela , Conrad Thomas , Husemann Cora C. , Kleo Karsten , Derêzanin Lorena , Dony Violaine , Farahani Saeed K. , Weiss Franziska , Branchi Federica , Kühl Anja A. , Schallenberg Simon , Weiner January , Elezkurtaj Sefer , Weixler Benjamin , Gröne Jörn , Siegmund Britta , Hummel Michael , Schumann Michael
Published: December 2023

Patients with ulcerative colitis (UC) and Crohn’s disease (CD) face a lifelong risk of developing colitis-associated carcinoma (CAC). Current insights into CAC development originate from murine CAC models, while human CAC studies primarily focus on mutational analysis of patient samples. Although the mutational landscape reveals distinct patterns and frequencies compared to colorectal cancer, it falls short in elucidating the inflammatory mechanisms of CAC development. Consequently, we adopted a multi-omics approach to unravel CAC carcinogenesis from an immunological perspective. Our data revealed a robust upregulation ofSPP1gene in CAC at both RNA and protein levels, expressed byCD68+macrophages. In vitro OPN stimulation demonstrated no direct effect on intestinal epithelial organoids. However, the mutually exclusive spatial location ofSPP1/OPN+macrophages andCD8+T cells suggests a crucial indirect role ofSPP1/OPNin mediating an immunosuppressive tumour microenvironment.
Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis
Authors: Vannan Annika , Lyu Ruqian , Williams Arianna L. , Negretti Nicholas M. , Mee Evan D. , Hirsh Joseph , Hirsh Samuel , Nichols David S. , Calvi Carla L. , Taylor Chase J. , Polosukhin Vasiliy. V. , Serezani Ana PM , McCall A. Scott , Gokey Jason J. , Shim Heejung , Ware Lorraine B. , Bacchetta Matthew J. , Shaver Ciara M. , Blackwell Timothy S. , Walia Rajat , Sucre Jennifer MS , Kropski Jonathan A. , McCarthy Davis J , Banovich Nicholas E.
Published: December 2023

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.
Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction
Authors: Moon Brianna F. , Zhou Iris Y. , Ning Yingying , Chen Yin-Ching I. , Fur Mariane Le , Shuvaev Sergey , Akam Eman A. , Ma Hua , Solsona Cesar Molinos , Weigand-Whittier Jonah , Rotile Nicholas , Hariri Lida P. , Drummond Matthew , Boice Avery T. , Zygmont Samantha E. , Sharma Yamini , Warburton Rod R. , Martin Gregory L. , Blanton Robert M. , Fanburg Barry L. , Hill Nicholas S. , Caravan Peter , Penumatsa Krishna C.
Published: December 2023

Background

Aging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model.

Methods

LV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen–targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and ΔLMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis.

Results

Allysine in the heart (22±5 (TAC), 13±5 (sham) nmol/g,P=0.02) and lungs (7.5±4 (TAC), 5.8±2 (sham) nmol/lung,P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29±15 (TAC), 6.1±4 (sham),P<0.0001) and ΔLMR (0.3±0.1 (TAC), 0.08±0.1 (sham),P<0.0001). Hyp in the heart (555±90 (TAC), 400±80 (sham) µg/g,P<0.0001) and lungs (189±63 (TAC), 143±31 (sham) µg/lung,P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8±0.1 (TAC), 1.6±0.2 (sham),P=0.02; LMR: 1.5±0.1 (TAC), 1.2±0.1 (sham),P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice.

Conclusions

Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.
Formation of the pyruvoyl-dependent proline reductase Prd fromClostridioides difficilerequires the maturation enzyme PrdH
Authors: Behlendorf Christian , Diwo Maurice , Neumann-Schaal Meina , Fuchs Manuela , Faber Franziska , Blankenfeldt Wulf
Published: December 2023

Stickland fermentation, the coupled oxidation and reduction of amino acid pairs, is a major pathway for obtaining energy in the nosocomial bacteriumClostridioides difficile. D-proline is the preferred substrate for the reductive path, making it not only a key component of the general metabolism but also impacting on the expression of the clostridial toxins TcdA and TcdB. D-proline reduction is catalyzed by the proline reductase Prd, which belongs to the pyruvoyl-dependent enzymes. These enzymes are translated as inactive proenzymes and require subsequent processing to install the covalently bound pyruvate. Whereas pyruvoyl formation by intramolecular serinolysis has been studied in unrelated enzymes, details about pyruvoyl generation by cysteinolysis such as in Prd are lacking. Here we show that Prd maturation requires a small dimeric protein that we have named PrdH. PrdH is co-encoded with the PrdA and PrdB subunits of Prd and also found in species producing similar reductases. By producing stable variants of PrdA and PrdB, we demonstrate that PrdH-mediated cleavage and pyruvoyl formation in the PrdA subunit require PrdB, which can be harnessed to produce active recombinant Prd for subsequent analyses. We further created PrdA- and PrdH-mutants to get insight into the interaction of the components and into the processing reaction itself. Finally, we show that deletion ofprdHinC. difficilerenders the corresponding mutant blind to proline, suggesting that this processing factor is essential for proline utilization. Due to the link between Stickland fermentation and pathogenesis, we suggest PrdH may be an attractive target for drug development.

Significance Statement

Energy conservation via Stickland fermentation was first described in the 1930s, yet information about the key enzyme of this process, Prd, is scarce, despite the fact that its central role in both metabolism and toxin production make it a promising potential drug target. Here we show how a small, previously overlooked protein that we named PrdH mediates the formation of the catalytically essential pyruvoyl-group in the active center of Prd.In vivostudies inC. difficileemphasize its critical importance in the utilization of proline. The known interplay between proline reduction and toxin production leads us to suggest PrdH as a potential drug target. Moreover, our findings open the door for further structural and functional studies with recombinantly produced active Prd.
Informing the need for a SARS-CoV-2 booster based upon the immune response among young, healthy adults to variants circulating during late 2023
Authors: Nguyen Huy C. , Lal Kerri G. , Balinsky Corey A. , Smith Lauren , Pan Li , Cheng Ying , Fox Isabella , Hontz Robert D. , Lizewski Stephen E. , Foo Hayley S. , Krebs Shelly J. , Sun Peifang , Letizia Andrew G.
Published: December 2023

COVID-19 remains a global public health challenge due to ongoing emergence of new immune-evasive SARS-CoV-2 variants, heterogeneous immunity, poor education campaigns, and suboptimal surveillance. In this cross-sectional study, we evaluated the adaptive immune responses in US active-duty service members who completed a COVID-19 primary vaccine series to 3 previously dominant variants (Ancestral, Delta, BA.5) and compared them to 3 variants currently circulating (XBB.1.5, EG.5, and BA.2.86). Analyses were performed based upon time (within or beyond 12 months) and type (vaccine or infection) of most recent exposure. Significant reduction was observed in binding antibodies, neutralization antibodies, memory B cells, and CD8+T cells against current circulating variants compared to previous dominant variants. The reduction in antibody response was more pronounced in those whose most recent exposure, regardless if vaccination or infection, was greater than 12 months from study enrollment. In contrast, the CD4+T cell response was largely consistent across all tested variants. Our study did not show that the type exposure in the last 12 months was a significant factor in determining the magnitude of immune responses. However, the antibody responses to circulating variants were decreased among participants who received the bivalent booster compared to those with an infection in the past 12 months, potentially due to immunological imprinting of the Ancestral strain. Administration of the new XBB.1.5-based booster is likely to enhance cross-reactive humoral immune responses against current SARS-CoV-2 circulating strains.
Towards cascading genetic risk in Alzheimer’s disease
Authors: Altmann Andre , Aksman Leon M , Oxtoby Neil P , Young Alexandra ,   ADNI, Alexander Daniel C , Barkhof Frederik , Shoai Maryam , Hardy John , Schott Jonathan M
Published: December 2023

Alzheimer’s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: Amyloid (A), Tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, where each of the biomarkers can be either positive (+) or negative (-). Over the past decades genome wide association studies have implicated about 90 different loci involved with the development of late onset Alzheimer’s disease. Here we investigate whether genetic risk for Alzheimer’s disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect.

Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer’s Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we employed Cox proportional hazards models to estimate the contribution ofAPOEand polygenic risk scores (beyondAPOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex, and years of education.

For progression from A-T- to A+T-, APOE-e4 burden showed significant effect (HR=2.88; 95% CI: 1.70-4.89; P<0.001), while polygenic risk did not (HR=1.09; 95% CI: 0.84-1.42; P=0.53). Conversely, for the transition from A+T- to A+T+, the APOE-e4 burden contribution was reduced (HR=1.62 95% CI: 1.05-2.51; P=0.031), while the polygenic risk showed an increased contribution (HR=1.73; 95% CI:1.27-2.36; P<0.001). The marginalAPOEeffect was driven by e4 homozygotes (HR=2.58; 95% CI: 1.05-6.35; P=0.039) as opposed to e4 heterozygotes (HR=1.74; 95% CI: 0.87-3.49; P=0.12).

The genetic risk for late-onset Alzheimer’s disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of transition between ATN stages, a better understanding of the molecular processes leading to Alzheimer’s disease as well as opening therapeutic windows for targeted interventions.
Diagnostic performance of serum CA-125 for overall and complicated acute appendicitis: a systematic review and meta-analysis
Authors: Arredondo Montero Javier , Pérez Riveros Blanca Paola , Bueso Asfura Oscar Emilio
Published: December 2023

Background

This study aimed to analyze the diagnostic performance of serum CA-125 in acute appendicitis (AA).

Methods

This review was registered in PROSPERO (CRD42023450988). We included prospective or retrospective original clinical studies evaluating the diagnostic performance of serum CA-125 in AA. A search was conducted in PubMed, Web of Science, Scopus, and OVID. Search terms and keywords were: (appendicitis OR appendectomy) AND (CA-125 OR CA125). Two independent reviewers selected the articles and extracted relevant data. Methodological quality was assessed using the QUADAS2 index. A synthesis of the results, standardization of the metrics, and three random-effect meta-analyses were performed.

Results

Five studies with data from 533 participants (including 219 patients with a confirmed diagnosis of AA and 107 controls) were included in this review. The random-effect meta-analysis of serum CA-125 (AA vs controls) included 5 articles (125 AA and 70 controls) and resulted in a non-significant mean difference [95% CI] of −6.80 [−20.51,6.92] U/mL (p=0.33). The meta-analysis by subgroups that included only male patients resulted in a significant mean difference [95% CI] of 3.48 [0.46,6.49] U/mL (p=0.02)

Conclusions

Although serum CA-125 does not appear to be a good overall marker for the diagnosis of AA, our subgroup analyses show that this marker could be useful for diagnosing AA in males. It also appears to be a potentially useful tool for discriminating complicated and uncomplicated AA. However, the limited number of included studies precludes drawing generalizable conclusions. Future prospective studies focused on males are required to confirm these findings.

Funding

None

Registration

PROSPERO (CRD42023450988).
Stage-specific expression patterns and co-targeting relationships among miRNAs in the developing mouse cerebral cortex
Authors: Todorov Hristo , Weißbach Stephan , Schlichtholz Laura , Mueller Hanna , Hartwich Dewi , Gerber Susanne , Winter Jennifer
Published: December 2023

microRNAs are particularly important during brain development, however, the composition and temporal dynamics of miRNA regulatory networks are not sufficiently characterized. Here, we performed small RNA sequencing of mouse embryonic cortical samples at E14, E17, and P0 as well as in neural progenitor cells differentiatedin vitrointo neurons. Using co-expression network analysis, we detected clusters of miRNAs that were co-regulated at distinct developmental stages. miRNAs such as miR-92a/b acted as hubs during early, and miR-124 and miR-137 during late neurogenesis. Notably, validated targets of P0 hub miRNAs were enriched for down-regulated genes related to stem cell proliferation, negative regulation of neuronal differentiation and RNA splicing, among others, suggesting that miRNAs are particularly important for modulating transcriptional programs of crucial factors that guide the switch to neuronal differentiation. As most genes contain binding sites for more than one miRNA, we furthermore constructed a co-targeting network where numerous miRNAs shared more targets than expected by chance. Using luciferase reporter assays, we demonstrated that simultaneous binding of miRNA pairs to neurodevelopmentally relevant genes exerted an enhanced transcriptional silencing effect compared to single miRNAs. Taken together, our study provides a comprehensive resource of miRNA longitudinal expression changes during corticogenesis. Furthermore, we highlight several potential mechanisms through which miRNA regulatory networks can shape embryonic brain development.
Transcriptional memory is conferred by combined heritable maintenance and local removal of selective chromatin modifications
Authors: Mikulski Pawel , Tehrani Sahar S.H. , Kogan Anna , Abdul-Zani Izma , Shell Emer , Ryan Brent J. , Jansen Lars E.T.
Published: December 2023

Interferon-γ (IFNγ) transiently activates genes involved in inflammation and innate immunity. A subset of targets maintain a mitotically heritable memory of prior IFNγ exposure resulting in hyperactivation upon reexposure. Here we discovered that the active chromatin marks H3K4me1, H3K14Ac and H4K16Ac are established during IFNγ priming and selectively maintained on a cluster of GBP genes for at least 7 days in dividing cells in the absence of transcription. The histone acetyltransferase KAT7 is required for the accelerated GBP reactivation upon reexposure to IFNγ. In naïve cells, we find the GBP cluster is maintained in low-level repressive chromatin marked by H3K27me3 limiting priming in a PRC2-dependent manner. Unexpectedly, IFNγ results in transient accumulation of this repressive mark but is then selectively depleted from primed GBP genes during the memory phase facilitating hyperactivation of primed cells. Furthermore, we identified a cis-regulatory element that makes transient, long-range contacts across the GBP cluster and acts as a repressor, primarily to curb the hyperactivation of previously IFNγ-primed cells. Combined our results identify the putative chromatin basis for long-term transcriptional memory of interferon signalling that may contribute to enhanced innate immunity.
Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus
Authors: Attar Ali Goktug , Paturej Jaroslaw , Banigan Edward J. , Erbas Aykut
Published: December 2023

Abnormalities in the shapes of mammalian cell nuclei are hallmarks of a variety of diseases, including progeria, muscular dystrophy, and various cancers. Experiments have shown that there is a causal relationship between chromatin organization and nuclear morphology. Decreases in heterochromatin levels, perturbations to heterochromatin organization, and increases in euchromatin levels all lead to misshapen nuclei, which exhibit deformations, such as nuclear blebs and nuclear ruptures. However, the polymer physical mechanisms of how chromatin governs nuclear shape and integrity are poorly understood. To investigate how heterochromatin and euchromatin, which are thought to microphase separatein vivo, govern nuclear morphology, we implemented a composite coarse-grained polymer and elastic shell model. By varying chromatin volume fraction (density), heterochromatin levels and structure, and heterochromatin-lamina interactions, we show how the spatial organization of chromatin polymer phases within the nucleus could perturb nuclear shape in some scenarios. Increasing the volume fraction of chromatin in the cell nucleus stabilizes the nuclear lamina against large fluctuations. However, surprisingly, we find that increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations in our simulations by a “wetting”-like interaction. In contrast, shape fluctuations are largely insensitive to the internal structure of the heterochromatin, such as the presence or absence of chromatin-chromatin crosslinks. Therefore, our simulations suggest that heterochromatin accumulation at the nuclear periphery could perturb nuclear morphology in a nucleus or nuclear region that is sufficiently soft, while stabilization of the nucleus via heterochromatin likely occurs through mechanisms other than chromatin microphase organization.
Building synthetic biosensors using red blood cell proteins
Authors: Dolberg Taylor B. , Gunnels Taylor F. , Ling Te , Sarnese Kelly A. , Crispino John D. , Leonard Joshua N.
Published: December 2023

As the use of engineered cell therapies expands from pioneering efforts in cancer immunotherapy to other applications, an attractive but less explored approach is the use of engineered red blood cells (RBCs). Compared to other cells, RBCs have a very long circulation time and reside in the blood compartment, so they could be ideally suited for applications as sentinel cells that enablein situsensing and diagnostics. However, we largely lack tools for converting RBCs into biosensors. A unique challenge is that RBCs remodel their membranes during maturation, shedding many membrane components, suggesting that an RBC-specific approach may be needed. Towards addressing this need, here we develop a biosensing architecture built on RBC membrane proteins that are retained through erythropoiesis. This biosensor employs a mechanism in which extracellular ligand binding is transduced into intracellular reconstitution of a split output protein (including either a fluorophore or an enzyme). By comparatively evaluating a range of biosensor architectures, linker types, scaffold choices, and output signals, we identify biosensor designs and design features that confer substantial ligand-induced signalin vitro. Finally, we demonstrate that erythroid precursor cells engineered with our RBC protein biosensors functionin vivo.This study establishes a foundation for developing RBC-based biosensors that could ultimately address unmet needs including non-invasive monitoring of physiological signals for a range of diagnostic applications.
Developmentally unique cerebellar processing prioritizes self- over other-generated movements
Authors: Richardson Angela M. , Sokoloff Greta , Blumberg Mark S.
Published: December 2023

Abstract

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self- generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) P8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses to twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.

SignificanceStatement

For adult animals to produce flexible and adaptive movements, they must distinguish self- from other-generated movements and learn to anticipate how their body moves through space. The computations required for this capacity occur within the cerebellar system. In early infancy, these computations are not yet established and must develop through sensorimotor experience. Here, we found that self-generated movements—particularly those movements occurring during active sleep—are a preferred source of that sensorimotor experience to the infant cerebellum. This preference appears to be unique to the infant cerebellum and helps us understand how that structure establishes its neural circuitry and functions.