bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting chemotherapy-induced thrombotoxicity by NARX neural networks and transfer learning
Authors: Steinacker Marie , Kheifetz Yuri , Scholz Markus
Published: August 2024

Background

Thrombocytopenia is a common side effect of cytotoxic chemotherapies, which is often dose-limiting. Predicting an individual’s risk is of high clinical importance, as otherwise, a small subgroup of patients limits dosages for the overall population for safety reasons.

Methods

We aim to predict individual platelet dynamics using non-linear auto-regressive networks with exogenous inputs (NARX). We consider different architectures of the NARX networks, namely feed-forward networks (FNN) and gated recurrent units (GRU). To cope with the relative sparsity of individual patient data, we employ transfer learning (TL) approaches based on a semi-mechanistic model of hematotoxicity. We use a large data set of patients with high-grade non-Hodgkin’s lymphoma to learn the respective models on an individual scale and to compare prediction performances with that of the semi-mechanistic model.

Results

Of the examined network models, the NARX with GRU architecture performs best. In comparison to the semi-mechanistic model, the network model can result in a substantial improvement of prediction accuracy for patients with irregular dynamics, given well-spaced measurements. TL improves individual prediction performances.

Conclusion

NARX networks can be utilized to predict an individual’s thrombotoxic response to cytotoxic chemotherapy treatment. For reasonable model learning, we recommend at least three well-spaced measurements per cycle: at baseline, during the nadir phase and during the recovery phase. We aim at generalizing our approach to other treatment scenarios and blood lineages in the future.
The Impact of Frailty Syndrome on Skeletal Muscle Histology: Preventive Effects of Exercise
Authors: Ji Fujue , Lee Hae Sung , Lee Haesung , Kim Jong-Hee
Published: August 2024

Aging-induced frailty syndrome significantly impairs skeletal muscle health, yet its impact on muscle histology remains unclear. This study investigates the histological alterations in muscle associated with frailty syndrome and evaluates the preventive effects of exercise. Mice were divided into groups based on age and condition, including an exercised group. Evaluated variables include body weight, lean mass ratio, myofiber size and number, extracellular matrix (ECM) content, and myosin heavy chain isoforms. Findings indicate that frailty syndrome increases body weight and ECM content, while reducing myofiber size and number, highlighting its negative impact on skeletal muscle histology. Notably, exercise effectively mitigated these adverse changes, suggesting its potential role in preventing skeletal muscle dysfunction associated with frailty syndrome.
Nervous system-wide analysis of all C. elegans cadherins reveals neuron-specific functions across multiple anatomical scales
Authors: Majeed Maryam , Liao Chien-Po , Hobert Oliver
Published: August 2024

Differential expression of cell adhesion proteins is a hallmark of cell type diversity across the animal kingdom. Gene family-wide characterization of their organismal expression and function are, however, lacking. We established an atlas of expression of the entire set of 12 cadherin gene family members in the nematode C. elegans, testing the hypothesis that members of this gene family define combinatorial expression codes that may drive nervous system assembly. This atlas reveals differential expression of genomically tagged cadherin genes across neuronal classes, a dichotomy between broadly- and narrowly-expressed cadherins, and several context-dependent temporal transitions in expression across development. Engineered mutant null alleles of cadherins were analyzed for defects in morphology, behavior, neuronal soma positions, neurite neighborhood topology and fasciculation, and localization of synapses in many parts of the nervous system. This analysis revealed a restricted pattern of neuronal differentiation defects at discrete subsets of anatomical scales, including a novel role of cadherins in experience-dependent electrical synapse formation. In total, our analysis results in novel perspectives on cadherin deployment and function.
Cysteine depletion triggers adipose tissue thermogenesis and weight-loss
Authors: Lee Aileen H. , Orliaguet Lucie , Youm Yun-Hee , Maeda Rae , Dlugos Tamara , Lei Yuanjiu , Coman Daniel , Shchukina Irina , Andhey Sairam , Smith Steven R. , Ravussin Eric , Stadler Krisztian , Hyder Fahmeed , Artyomov Maxim N. , Sugiura Yuki , Dixit Vishwa Deep
Published: August 2024

Dietary interventions such as caloric restriction (CR)1and methionine restriction2that prolong lifespan induce the ‘browning’ of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health3,4. However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans5reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH)6, the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
Iota oscillations (25-35 Hz) during wake and REM sleep in children and young adults
Authors: Snipes Sophia
Published: August 2024

1

High-frequency brain oscillations in humans are currently categorized into beta (13-30 Hz) and gamma (>30 Hz). Here, I introduce a new class of oscillations between 25 and 35 Hz, which I propose to call “iota.” Iota oscillations have low amplitudes but can still be measured with surface electroencephalography (EEG). Within an individual, iota has a narrow spectral bandwidth of 2-4 Hz, thus distinguishing it from broadband beta and gamma. Iota oscillations occur as sustained bursts during both wakefulness and REM sleep but do not appear during NREM sleep. They are only found in a minority of individuals, more in children than in adults. Overall, iota oscillations are challenging to detect but could serve as a marker of both brain development and states of vigilance.
Multiple Notch ligands in the synchronization of the segmentation clock
Authors: Wappner Marcos , Uriu Koichiro , Oates Andrew C. , Morelli Luis G.
Published: August 2024

Notch signaling is a ubiquitous and versatile intercellular signaling system that drives collective behaviors and pattern formation in biological tissues. During embryonic development, Notch is involved in generation of collective biochemical oscillations that form the vertebrate body segments, and its failure results in embryonic defects. Notch ligands of the Delta family are key components of this collective rhythm, but it is unclear how different Delta ligands with distinct properties contribute to relaying information among cells. Motivated by the zebrafish segmentation clock, in this work we propose a theory describing interactions between biochemical oscillators, where Notch receptor is bound by both oscillatory and nonoscillatory Delta ligands. Based on previous in vitro binding studies, we first consider Notch activation by Delta dimers. This hypothesis is consistent with experimental observations in conditions of perturbed Notch signaling. Then we test an alternative hypothesis where Delta monomers directly bind and activate Notch, and show that this second model can also describe the experimental observations. We show that these two hypotheses assign different roles for a non-oscillatory ligand, as a binding partner or as a baseline signal. Finally, we discuss experiments to distinguish between the two scenarios. Broadly, this work highlights how a multiplicity of ligands may be harnessed by a signaling system to generate versatile responses.
Accelerated Limbal Epithelial Differentiation of Human Induced Pluripotent Stem Cells Using a Defined Keratinocyte Serum-Free Medium
Authors: Roshandel Danial , Alvarez-Palomo Belén , Zaw Khine , Zhang Dana , Edel Michael J , Wong Evan N , Wiffen Steven , Chen Fred K , Morgan William , McLenachan Samuel
Published: August 2024

Purpose

Treatment of bilateral limbal stem cell deficiency (LSCD) is challenging due to the limited autologous stem cell sources. This study aimed to differentiate human induced pluripotent stem cells (hiPSCs) into limbal epithelial stem cells (LESCs) using a defined keratinocyte serum-free medium (DKSFM).

Methods

A fully characterized hiPSC line was committed to ectodermal differentiation using Essential 6 (E6) medium supplemented with 10 µM Y-27632 (Day 1), 10 µM SB-505124 plus 50 ng/ml bFGF (Day 2) and 25 ng/ml BMP-4 (Days 3 and 4). Differentiation was continued in DKSFM for an additional 21 days. Quantitative PCR (qPCR) and/or immunocytochemistry (ICC) for pluripotency, proliferation, LESC, and corneal epithelial markers were performed on samples collected at days 5, 10, 15, and 25 (D5 to D25) and compared with undifferentiated hiPSCs (UD).

Results

qPCR revealed a significant decrease in the expression ofOCT4andNANOGand a significant increase inABCG2andTP63following ectodermal induction (i.e., D5), compared with UD (P < 0.05). The expression levels ofKi67,ABCG2,TP63, andCK14were significantly higher at D10, compared with D5 and D25 (P < 0.05). The ratio of p63α-positive cells was 71% and 56% in D10 and D15 cells, respectively (P < 0.05).

Discussion

Our method resulted in a limited but rapid differentiation of hiPSCs into LESC-like cells. The LESC-like cells appeared as early as 5 days following ectodermal induction and their population peaked after 10 days. Upon further optimization and validation, DKSFM can be used for rapid limbal epithelial differentiation of hiPSCs.
Tokenized and Continuous Embedding Compressions of Protein Sequence and Structure
Authors: Lu Amy X. , Yan Wilson , Yang Kevin K. , Gligorijevic Vladimir , Cho Kyunghyun , Abbeel Pieter , Bonneau Richard , Frey Nathan
Published: August 2024

Existing protein machine learning representations typically model either the sequence or structure distribution, with the other modality implicit. The latent space of sequence-to-structure prediction models such as ESMFold represents thejoint distributionof sequence and structure; however, we find these embeddings to exhibit massive activations, whereby some channels have values 3000× higher than others, regardless of the input. Further, on continuous compression schemes, ESMFold embeddings can be reduced by a factor of 128× along the channel and 8× along the length, while retaining structure information at <2Å scale accuracy, and performing competitively on protein function and localization benchmarks. On discrete compression schemes, we construct a tokenized all-atom structure vocabulary that retains high reconstruction accuracy, thus introducing atokenized representation of all-atom structure that can be obtained from sequence alone. We term this series of embeddings as CHEAP (Compressed Hourglass Embedding Adaptations of Proteins) embeddings, obtained via the HPCT (Hourglass Protein Compression Transformer) architecture. CHEAP is a compact representation of both protein structure and sequence, sheds light on information content asymmetries between sequence and structure, democratizes representations captured by large models, and is designed to have flexible downstream applications such as generation, search, and prediction.
Molecular Glue-Design-Evaluator (MOLDE): An Advanced Method for In-Silico Molecular Glue Design
Authors: Ben Geoffrey A S , Agrawal Deepak , Kulkarni Nagaraj M , Manonmani G
Published: August 2024

Protein function modulation using small molecule binding is an important therapeutic strategy for many diseases. However, many proteins remain undruggable due to lack of suitable binding pockets for small molecule binding. Proximity induced protein degradation using molecular glues has recently been identified as an important strategy to target undruggable proteins. Molecular glues were discovered serendipitously and as such currently lack an established approach for in-silico driven rationale design. In this work, we aim to establish an in-silico method for designing molecular glues. To achieve this, we leverage known molecular glue-mediated ternary complexes and derive a rationale for in-silico design of molecular glues. Establishing an in-silico rationale for molecular glue design would significantly contribute to the literature and accelerate the discovery of molecular glues for targeting previously undruggable proteins. Our work presented here and named as Molecular Glue-Designer-Evaluator (MOLDE) contributes to the growing literature of in-silico approaches to drug design in-silico literature.
Molecular Identification and Antimicrobial Potential of Endophytic Fungi Against Some Grapevine Pathogens
Authors: Nashat Lava H. , Haleem Raed A. , Ali Shayma H.
Published: August 2024

In the Duhok province of the Kurdistan region, the plant speciesVitis viniferahas been explored as a habitat for diverse endophytic microorganisms across various ecological environments. During the period from 2021 to 2022, a total of 600 samples were collected from four distinct locations: Bagera, Besfke, Barebhar, and Atrush. From these samples, twelve endophytic fungal species were isolated, includingAspergillus flavus, Botryosphaeria dothidea, Fusarium oxysporum, Fusarium ruscicol, Fusarium venenatum, Chaetomium globosum, Clonostachys rosea, Mucor racemosus, Penicillium glabrum, Aspergillus terreus, Aspergillus ustus, andAspergillus niger. These fungi are recognized for their potential as biocontrol agents against grapevine trunk diseases and grape rotting fungi, which pose significant risks to grapevine health and productivity. Based on ITS and SSU sequencing, molecular identification confirmed these fungi’s presence with sequence identities ranging from 99% to 100%. Phylogenetic analysis revealed that these endophytes could be categorized into five main clusters (A, B, C, D, and E), showing high intra-group similarity. Utilizing the Dual Culture method, the endophytePaecilomyces maximusdemonstrated a 70.83% inhibition rate againstIlyonectria destructans. In the Food Poisoning method,A. flavusandP. maximusemerged as the most effective inhibitors ofIlyonectria destructans, whereasA. terreus, M. racemosus, andP. maximusachieved complete inhibition (100%) ofBotrytis cinerea. Additionally,M. racemosuswas identified as the most effective biocontrol agent againstNeoscytalidium dimidiatum.
Persistence of respiratory, enteric, and fecal indicator viruses in fecal sludge from on-site sanitation in Dakar, Senegal
Authors: Mendoza Grijalva Lorelay , Seck Alsane , Roldan-Hernandez Laura , Graham Katherine E. , Boehm Alexandria B. , Tarpeh William A.
Published: August 2024

As wastewater-based epidemiology (WBE) broadens its focus to include prevalent diseases with significant global health impact, existing surveillance systems concentrate on sewer-based infrastructure, which excludes the 2.7 billion people using non-sewered systems. To address this gap, our study explores the potential of fecal sludge treatment plants (FSTPs) for WBE, emphasizing the stability of virus RNA targets within pooled fecal sludge. We screened fecal sludge from a centralized treatment facility in Dakar, Senegal for SARS-CoV-2, human norovirus (HuNoV), and microbial source trackers (MSTs) pepper mild mottle virus (PMMoV) and tomato brown rugose fruit virus (ToBRFV). Decay kinetics of genomic RNA markers from these viruses were examined at 4 °C, 15 °C, and 30 °C over 70 days. Results indicate high persistence of viral targets in fecal sludge (T90 value of 3.3 months for exogenous SARS-CoV-2 N1 and N2, 6.2 months for ToBRFV), with all targets detected throughout the 70-day experiment under various temperatures with limited decay (<1 log10 reduction). This study addresses a crucial gap in understanding virus persistence in on-site sanitation systems by providing essential decay rate constants for effective target detection. Our results indicate that sampling at centralized facilities treating fecal sludge from on-site sanitation could facilitate localized pathogen surveillance in low-income settings.

Highlights

Investigation of the persistence of SARS-CoV-2, HuNoV, PMMoV, and ToBRFV genomic RNA in pooled fecal sludge derived from on-site sanitation systems.

Novel microbial source tracker (MST), ToBRFV, exhibited comparable abundance to PMMoV, a well-established MST, in fecal sludge.

No significant decay observed for HuNoV and PMMoV over 70 days at all temperature conditions (4, 15, and 30 °C).

SARS-CoV-2 N1 and N2 showed T90values of 3.3 months at 30 °C.

Fecal sludge treatment plants offer a centralized sampling location for wastewater-based epidemiology, providing a strategic approach for monitoring public health.

Graphical Abstract
The transcriptome of CD14+CD163-HLA-DRlowmonocytes predicts mortality in Idiopathic Pulmonary Fibrosis
Authors: Karampitsakos Theodoros , Tourki Bochra , Jia Minxue , Perrot Carole Y. , Visinescu Bogdan , Zhao Amy , Unterman Avraham , Tzouvelekis Argyris , Bandyopadhyay Debabrata , Juan-Guardela Brenda M. , Prasse Antje , Noth Imre , Liggett Stephen , Kaminski Naftali , Benos Panayiotis V. , Herazo-Maya Jose D.
Published: August 2024

Rationale

The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown.

Objectives

To determine immune-cell-specific transcriptomic profiles associated with IPF mortality.

Methods

We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38).

Measurements and main results

Cox-regression models demonstrated that 230 genes from CD14+CD163-HLA-DRlowcirculating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14+CD163-HLA-DRlowmonocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genesCD28,ICOS,ITKandLCK(Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001).

Conclusions

The transcriptome of CD14+CD163-HLA-DRlowmonocytes is associated with increased IPF mortality.
Genomic ascertainment ofCHEK2-related cancer predisposition
Authors: Kim Sun Young , Kim Jung , Ramos Mark , Haley Jeremy , Smelser Diane , Rao H. Shanker , Mirshahi Uyenlinh L. ,   Geisinger-Regeneron DiscovEHR Collaboration, Graubard Barry I. , Katki Hormuzd A. , Carey David , Stewart Douglas R.
Published: August 2024

Purpose

There is clear evidence that deleterious germline variants inCHEK2increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk inCHEK2germline pathogenic variant heterozygotes.

Patients and Methods

GermlineCHEK2variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765)and Geisinger MyCode (n=170,503). Variants were classified as per American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria. Heterozygotes harbored aCHEK2pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benignCHEK2variation or wildtypeCHEK2. Tumor phenotype and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction.

Results

InCHEK2heterozygotes in both MyCode and UK Biobank, there was a significant excess risk of all cancers tested, including breast cancer (C50; OR=1.54 and 1.84, respectively), male genital organ cancer (C60-C63; OR=1.61 and 1.77 respectively), urinary tract cancer (C64-C68; OR=1.56 and 1.75, respectively) and lymphoid, hematopoietic, and related tissue cancer (C81-C96; OR=1.42 and 2.11, respectively). Compared to controls, age-dependent cancer penetrance inCHEK2heterozygotes was significantly younger in both cohorts; no significant difference was observed between the penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased inCHEK2heterozygotes in UK Biobank but there was no statistical difference in MyCode.

Conclusion

Using genomic ascertainment in two population-scale cohorts, this investigation quantified the prevalence, penetrance, cancer phenotype and survival inCHEK2heterozygotes. Tailored treatment options and surveillance strategies to manage those risks are warranted.
Persistent PTSD symptoms are associated with plasma metabolic alterations relevant to long-term health: A metabolome-wide investigation in women
Authors: Zhu Yiwen , Shutta Katherine H. , Huang Tianyi , Balasubramanian Raji , Zeleznik Oana A. , Clish Clary B. , Ávila-Pacheco Julián , Hankinson Susan E. , Kubzansky Laura D.
Published: August 2024

Background

Posttraumatic stress disorder (PTSD) is characterized by severe distress and associated with cardiometabolic diseases. Studies in military and clinical populations suggest dysregulated metabolomic processes may be a key mechanism. Prior work identified and validated a metabolite-based distress score (MDS) linked with depression and anxiety and subsequent cardiometabolic diseases. Here, we assessed whether PTSD shares metabolic alterations with depression and anxiety and also if additional metabolites are related to PTSD.

Methods

We leveraged plasma metabolomics data from three subsamples nested within the Nurses’ Health Study II, including 2835 women with 2950 blood samples collected across three timepoints (1996-2014) and 339 known metabolites consistently assayed by mass spectrometry-based techniques. Trauma and PTSD exposures were assessed in 2008 and characterized as follows: lifetime trauma without PTSD, lifetime PTSD in remission, and persistent PTSD symptoms. Associations between the exposures and the MDS or individual metabolites were estimated within each subsample adjusting for potential confounders and combined in random-effects meta-analyses.

Results

Persistent PTSD symptoms were associated with higher levels of the previously developed MDS for depression and anxiety. Out of 339 metabolites, we identified nine metabolites (primarily elevated glycerophospholipids) associated with persistent symptoms (false discovery rate<0.05). No metabolite associations were found with the other PTSD-related exposures.

Conclusions

As the first large-scale, population-based metabolomics analysis of PTSD, our study highlighted shared and distinct metabolic differences linked to PTSD versus depression or anxiety. We identified novel metabolite markers associated with PTSD symptom persistence, suggesting further connections with metabolic dysregulation that may have downstream consequences for health.
Associations of Serum GDF-15 Levels with Physical Performance, Mobility Disability, Cognition, Cardiovascular Disease, and Mortality in Older Adults
Authors: Webber Katey , Patel Sheena , Kizer Jorge R. , Eastell Richard , Psaty Bruce M. , Newman Anne B. , Cummings Steven R.
Published: August 2024

Background

Growth differentiation factor 15 (GDF-15) is a member of the TGFβ superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated.

Methods

We pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality.

Results

The pooled study cohort had a mean age of 75.4 +/−4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22]).

Conclusions

GDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.
cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation
Authors: Yu Sheeline , Hu Buqu , Sun Ying , Peng Xue Yan , Lee Chris J. , Woo Samuel , McGovern John , Zielonka Jana , Saber Tina , Ghincea Alexander , Gandhi Shifa , Walia Anjali , Pivarnik Taylor , Ishikawa Genta , Shuai Shao , Sun Huanxing , Gunes Baran Ilayda , Kujawski Sophia , Perez Stephanie , Odell William , Hinchcliff Monique , Varga John , Bostwick Carol Feghali- , Sauler Maor , Gomez Jose L. , Ryu Changwan , Herzog Erica L.
Published: August 2024

Objective

The lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model.

Methods

Expression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts.CGASactivation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFβ1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs) via qRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model.

Results

SSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFβ1 or mechanical stimuli. In these settings, and in human PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model.

Conclusion

cGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.
Effectiveness of digital health interventions against COVID-19 misinformation: a systematic realist review of intervention trials
Authors: Dickinson Robert , Makowski Dominique , van Marwijk Harm , Ford Elizabeth
Published: August 2024

Misinformation is a growing concern worldwide, particularly in public health following the COVID-19 pandemic in which misinformation has been attributed to tens of thousands of unnecessary deaths. Therefore a search for effective interventions against misinformation is underway, with widely varying proposed interventions, measures of efficacy, and groups targeted for intervention. This realist systematic review of proposed interventions against COVID-19 misinformation assesses the studies themselves, the characteristics and effectiveness of the interventions proposed, the durability of effect, and the circumstances and contexts within which these interventions function. We searched several databases for studies testing interventions published from 2020 onwards. The search results were sorted by eligibility, with eligible studies then being coded by themes and assessed for quality. Twenty-six studies were included, representing eight types of intervention. The results are promising to the advantages of game-type interventions, with other types scoring poorly on either scalability or impact. Backfire effects and effects on subgroups were reported on intermittently in the included studies, showing the advantages of certain interventions for subgroups or contexts. No one intervention appears sufficient by itself, therefore this study recommends the creation of packages of interventions by policymakers, who can tailor the package for contexts and targeted groups. There was high heterogeneity in outcome measures and methods, making comparisons between studies difficult; this should be a focus in future studies. Additionally, the theoretical and intervention literatures need connecting for greater understanding of the mechanisms at work in the interventions. Lastly, there is a need for work more explicitly addressing political polarisation and its role in the belief and spread of misinformation. This study contributes toward the expansion of realist review approaches, understandings of COVID-19 misinformation interventions, and broader debates around the nature of politicisation in contemporary misinformation.
Country Level Incidence of Alzheimer Disease and Related Dementias is Associated with Increased Omega6 PUFA Consumption
Authors: Ciesielski Timothy H. , Tosto Giuseppe , Durodoye Razaq O. , Rajabali Farid , Akinyemi Rufus O. , Byrd Goldie S. , Bush William S. , Kunkle Brian W. , Reitz Christiane , Vance Jeffery M. , Pericak-Vance Margaret A. , Haines Jonathan L. , Williams Scott M.
Published: August 2024

INTRODUCTION

Clinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study.

METHODS

Mean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents. Penalized spline regression and multivariable-adjusted linear regression, including a lag between intake and incidence, were used to assess the relationships between five lipid intakes and ASAIR. Validation was conducted using longitudinal within-country changes between 1990 and 2019.

RESULTS

Omega6 Polyunsaturated-Fatty-Acid(PUFA) intake exhibited a positive linear relationship with ASAIR(multivariable-adjusted model: β=2.44; 95%CI: 1.70, 3.19; p=1.38×10-9). ASAIR also increased with saturated-fat, trans-fat, and dietary-cholesterol up to a threshold. The association between Omega6-PUFA and ASAIR was confirmed using longitudinal intake changes.

DISCUSSION

Decreasing Omega6-PUFA consumption on the country-level may have substantial benefits in reducing the country-level burden of AD.
Combining short and long read sequencing technologies to identify SARS-CoV-2 variants in wastewater
Authors: Jayme Gabrielle , Liu Ju-Ling , Galvez Jose Hector , Reiling Sarah Julia , Aydin Sukriye Celikkol , N’Guessan Arnaud , Lee Sally , Chen Shu-Huang , Tsitouras Alexandra , Sanchez-Quete Fernando , Maere Thomas , Goitom Eyerusalem , Hachad Mounia , Mercier Elisabeth , Loeb Stephanie Katharine , Vanrolleghem Peter , Dorner Sarah , Delatolla Robert , Shapiro B. Jesse , Frigon Dominic , Ragoussis Jiannis , Snutch Terrance P.
Published: August 2024

During the COVID-19 pandemic, the monitoring of SARS-COV-2 RNA in wastewater was used to track the evolution and emergence of variant lineages and gauge infection levels in the community, informing appropriate public health responses without relying solely on clinical testing. As more sublineages were discovered, it increased the difficulty in identifying distinct variants in a mixed population sample, particularly those without a known lineage. Here, we compare two next-generation sequencing technologies, Illumina and Nanopore, in order to determine their efficacy at detecting variants of differing abundance, using 248 wastewater samples from various Quebec and Ontario cities. Our study used two analytical approaches to identify main variants in the samples: the presence of signature and marker mutations, and the co-occurrence of signature mutations within the same amplicon. We observed that each sequencing method detected certain variants at different frequencies as each method preferentially detects mutations of distinct variants. Illumina sequencing detected more mutations with a predominant lineage that is in low abundance across the population or unknown for that time period, while Nanopore sequencing had a higher detection rate of mutations that are predominantly found in the high abundance B.1.1.7 (Alpha) lineage as well as a higher sequencing rate of co-occurring mutations in the same amplicon. We present a workflow that integrates short read and long read sequencing to improve the detection of SARS-CoV-2 variant lineages in mixed population samples, such as wastewater.
NF-κB Mediated Disruption of Pancreatic Signaling Pathways and its Implications for the Risk of Pancreatic Adenocarcinoma: a systematic review
Authors: Shafi Ovais , Rajpar Rahimeen , Aakash  , Waqas Muhammad , Haseeb Madiha , Raveena  , Kumari Madhurta , Kumar Ajay , Kumari Muskan , Yaqub Muhammad Danial
Published: August 2024

Objective

The objective of this study is to determine how NF-κB-mediated inflammation disrupts pancreatic signaling pathways and the resultant increase in the risk of Pancreatic Adenocarcinoma.

Background

Pancreatic adenocarcinoma’s severity and poor prognosis underscore the critical role of NF-κB-mediated inflammation in disease progression. NF-κB activation disrupts key pancreatic signaling pathways by promoting cell proliferation, inhibiting differentiation, and facilitating oncogenic transformation. Understanding these mechanisms is essential for developing targeted therapies that mitigate NF-κB-induced damage, improve early detection through biomarkers, and enhance treatment outcomes for pancreatic cancer patients.

Methods

Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to investigate how NF-κB-mediated inflammation disrupts pancreatic signaling pathways and the resultant increase in the risk of Pancreatic Adenocarcinoma. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate the research question. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Results

NF-κB-mediated inflammation significantly disrupts several critical pancreatic signaling pathways, leading to oncogenic transformations and increased risk of pancreatic adenocarcinoma. Specifically, NF-κB activation alters Notch signaling, causing abnormal cell differentiation; disrupts Wnt and Shh pathways, enhancing cellular proliferation; and perturbs FGF and TGF-β pathways, leading to impaired cellular homeostasis. Additionally, NF-κB interferes with BMP signaling, contributing to dysregulated cell growth; modulates the PI3K/Akt/mTOR pathway, promoting cell survival and tumor growth; affects JAK/STAT signaling, resulting in enhanced inflammatory responses and tumor progression; and disrupts Hippo pathway components, which normally regulate organ size and inhibit tumorigenesis.

Conclusion

NF-κB-mediated inflammation disrupts critical pancreas signaling pathways—Notch, Wnt, Hippo, JAK/STAT, and others—promoting cell survival, proliferation, and oncogenic transformation. This dysregulation, seen in chronic inflammation, elevates pancreatic adenocarcinoma risk by fostering a tumorigenic microenvironment. These interactions highlight NF-κB as a central player in pancreatic cancer pathogenesis. Targeting NF-κB and associated pathways emerges as crucial for therapeutic strategies aimed at mitigating inflammatory damage and improving outcomes in pancreatic adenocarcinoma treatment.
Stochastic Wiring of Cell Types Enhances Fitness by Generating Phenotypic Variability
Authors: Lachi Divyansha , Huang Ann , Mavor-Parker Augustine N. , Ghosh Arna , Richards Blake , Zador Anthony
Published: August 2024

The development of neural connectivity is a crucial biological process that gives rise to diverse brain circuits and behaviors. Neural development is a stochastic process, but this stochasticity is often treated as a nuisance to overcome rather than as a functional advantage. Here we use a computational model, in which connection probabilities between discrete cell types are genetically specified, to investigate the benefits of stochasticity in the development of neural wiring. We show that this model can be viewed as a generalization of a powerful class of artificial neural networks—Bayesian neural networks—where each network parameter is a sample from a distribution. Our results reveal that stochasticity confers a greater benefit in large networks and variable environments, which may explain its role in organisms with larger brains. Surprisingly, we find that the average fitness over a population of agents is higher than a single agent defined by the average connection probability. Our model reveals how developmental stochasticity, by inducing a form of non-heritable phenotypic variability, can increase the probability that at least some individuals will survive in rapidly changing, unpredictable environments. Our results suggest how stochasticity may be an important feature rather than a bug in neural development.
Cell wall composition in relation to photosynthesis across land plants’ phylogeny: crops as outliers
Authors: Roig-Oliver Margalida , Flexas Jaume , Clemente-Moreno María José , Carriquí Marc
Published: August 2024

In the present study, we combine published and novel data on cell wall composition and photosynthesis limitations, including data for all the major land plant’s phylogenetic groups. We provide novel evidence on the importance of cell wall composition in determining mesophyll conductance to CO2diffusion (gm) across land plants’ phylogeny. We address the hypothesis that the pectin fraction of total major cell wall compounds is positively related togmand, consequently, to photosynthesis, when pooling species from across the entire phylogeny.

The role of cell wall composition in photosynthesis has only recently been proposed. Apparently contradictory results have been reported, but previous studies were often limited to single or closely related species. This is the very first report to show general relationships by considering species spanning the entire phylogeny of land plants.

This study identifies a clear biochemical basis—one that can be traced back to specific genes— for a large component of mesophyll conductance and, thus, photosynthetic capacity. It opens new avenues for improving the photosynthesis of terrestrial plants. Additionally, it suggests that current crops are already optimized and even uncoupled from these general relationships, raising questions about the regulation ofgmin crop species.
The novel ECM protein SNED1 mediates cell adhesion via the RGD-binding integrins α5β1 and αvβ3
Authors: Pally Dharma , Kapoor Nandini , Naba Alexandra
Published: August 2024

The extracellular matrix (ECM) is a complex meshwork comprising over 100 proteins. It serves as an adhesive substrate for cells and, hence, plays critical roles in health and disease. We have recently identified a novel ECM protein, SNED1, and have found that it is required for neural crest cell migration and craniofacial morphogenesis during development and in breast cancer, where it is necessary for the metastatic dissemination of tumor cells. Interestingly, both processes involve the dynamic remodeling of cell-ECM adhesions via cell surface receptors. Sequence analysis revealed that SNED1 contains two amino acid motifs, RGD and LDV, known to bind integrins, the largest class of ECM receptors. We thus sought to investigate the role of SNED1 in cell adhesion. Here, we report that SNED1 mediates breast cancer and neural crest cell adhesion via its RGD motif. We further demonstrate that cell adhesion to SNED1 is mediated by the RGD integrins α5β1 and αvβ3. These findings are a first step toward identifying the signaling pathways activated downstream of the SNED1-integrin interactions guiding craniofacial morphogenesis and breast cancer metastasis.

SUMMARY STATEMENT

We report that the novel extracellular matrix protein SNED1 promotes the adhesion of breast cancer cells and neural crest cells via interaction with α5β1 and αvβ3 integrins, the first SNED1 receptors identified to date.
In vitrobio-activity of three potential antagonistic fungi against selected plant pathogens in Ghana
Authors: Dwamena Elvis , Awuah Richard Tuyee , Agbetiameh Daniel , Aidoo Atta Kwesi
Published: August 2024

In the quest of developing sustainable strategies for the management of diseases affecting major crop species, this study screened three antagonists,viz. Trichoderma asperellum.,Penicillium citrinum. andMyxotrichum stipitatum., for inhibitory activity against seven plant pathogens,viz. Pestalotia heterocornis, Curvularia eragrostidis, Lasiodiplodia theobromae, Sclerotium rolfsii, Colletotrichum gloeosporioides, Aspergillus flavus,andA. parasiticuson Potato Dextrose Agar (PDA) plates using the dual culture method. For each potential antagonistic fungus-pathogen combination, four replicated dual culture plates were prepared and laid out in a completely randomized design (CRD). Control plates with only the pathogens and no antagonistic fungi were also established. All assay plates were incubated at 28 ℃ (approx.) and the diameters of the pathogen in both the dual culture and control plates were measured at 6, 10 and 14 days. Percentage inhibition of fungal pathogens were calculated and used to draw a colony reduction curve for each antagonist-pathogen interaction. Areas Under the Colony Reduction Curves (AUCRC’s) were calculated. Of the three antagonistic fungi tested,Trichoderma asperellum. was the most effective in inhibiting colony diameters of all seven pathogens with an average AUCRC of 813.19 % days, followed by thePenicillium citrinum. (519.25 % days). The weakest antagonist wasMyxotrichum stipitatumsp. with an AUCRC of 440.6. % days. The results of the study suggest thatT.asperellumandP.citrinumcould be exploited for plant disease biocontrol.
Peripheral membrane protein endophilin B1 probes, perturbs and permeabilizes lipid bilayers
Authors: Thorlacius Arni , Rulev Maksim , Sundberg Oscar , Sundborger-Lunna Anna
Published: August 2024

Bin/Amphiphysin/Rvs (BAR) domain containing proteins are cytosolic, peripheral membrane proteins that regulate the curvature of membranes in eukaryotic cells. BAR protein endophilin B1 plays a key role in multiple cellular processes critical for oncogenesis, including autophagy and apoptosis. Amphipathic regions in endophilin B1 drive membrane association and tubulation through membrane scaffolding. Our understanding of exactly how BAR proteins like endophilin B1 promote highly diverse intracellular membrane remodeling events in the cell is severely limited due to lack of high-resolution structural information. Here we present the highest resolution cryo-EM structure of a BAR protein to date and the first structures of a BAR protein bound to nanodiscs. Using neural networks, we can effectively sort particle species of different stoichiometries, revealing the tremendous flexibility of post-membrane binding, pre-polymer BAR dimer organization and membrane deformation. We also show that endophilin B1 efficiently permeabilizes negatively charged liposomes that contain mitochondria-specific lipid cardiolipin and propose a new model for Bax-mediated cell death.
A Simplified Method for Comprehensive Capture of theStaphylococcus aureusProteome
Authors: Mustor Emilee M. , Wohlfahrt Jessica , Guergues Jennifer , Stevens Stanley M. , Shaw Lindsey Neil
Published: August 2024

Staphylococcus aureusis a major human pathogen causing myriad infections in both community and healthcare settings. Although well studied, a comprehensive exploration of its dynamic and adaptive proteome is still somewhat lacking. Herein, we employed streamlined liquid- and gas-phase fractionation with PASEF analysis on a TIMS-TOF instrument to expand coverage and explore theS. aureusdark proteome. In so doing, we captured the most comprehensiveS. aureusproteome to date, totaling 2,231 proteins (85.6% coverage), using a significantly simplified process that demonstrated high reproducibility with minimal input material. We then showcase application of this library for differential expression profiling by investigating temporal dynamics of theS. aureusproteome. This revealed alterations in metabolic processes, ATP production, RNA processing, and stress-response proteins as cultures progressed to stationary growth. Notably, a significant portion of the library (94%) and proteome (80.5%) was identified by this single-shot, DIA-based analysis. Overall, our study shines new light on the hiddenS. aureusproteome, generating a valuable new resource to facilitate further study of this dangerous pathogen.