bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlled release of microorganisms from engineered living materials
Authors: Kalairaj Manivannan Sivaperuman , George Iris , George Sasha M. , Farfán Sofía E. , Lee Yoo Jin , Rivera-Tarazona Laura K. , Wang Suitu , Abdelrahman Mustafa K. , Tasmim Seelay , Dana Asaf , Zimmern Philippe E. , Subashchandrabose Sargurunathan , Ware Taylor H.
Published: September 2024

Probiotics offer therapeutic benefits by modulating the local microbiome, the host immune response, and the proliferation of pathogens. Probiotics have the potential to treat complex diseases, but their persistence or colonization is required at the target site for effective treatment. Although probiotic persistence can be achieved by repeated delivery, no biomaterial that releases clinically relevant doses of metabolically active probiotics in a sustained manner has been previously described. Here, we encapsulate stiff probiotic microorganisms within relatively less stiff hydrogels and show a generic mechanism where these microorganisms proliferate and induce hydrogel fracture, resulting in microbial release. Importantly, this fracture-based mechanism leads to microorganism release with zero-order release kinetics. Using this mechanism, small (∼1 μL) engineered living materials (ELMs) release >108colony-forming-units (CFUs) ofE. coliin 2 h. This release is sustained for at least 10 days. Cell release can be varied by more than three orders of magnitude by varying initial cell loading and modulating the mechanical properties of encapsulating matrix. As the governing mechanism of microbial release is entirely mechanical, we demonstrate controlled release of model Gram-negative, Gram-positive, and fungal probiotics from multiple hydrogel matrices.

SIGNIFICANCE

Probiotics offer therapeutic benefits and have the potential to treat complex diseases, but their persistence at the target site is often required for effective treatment. Although probiotic persistence can be achieved by repeated delivery, no biomaterial that releases metabolically active probiotics in a sustained manner has been developed yet. This work demonstrates a generic mechanism where stiff probiotics encapsulated within relatively less stiff hydrogels proliferate and induce hydrogel fracture. This allows a zero-order release of probiotics which can be easily controlled by adjusting the properties of the encapsulating matrices. This generic mechanism is applicable for a wide range of probiotics with different synthetic matrices and has the potential to be used in the treatment of a broad range of diseases.
Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion moleculesbeat-Ia/CADM2
Authors: Mace Kyla , Zimmerman Amber , Chesi Alessandra , Doldur-Balli Fusun , Kim Hayle , Almeraya Del Valle Erika , Pack Allan I. , Grant Struan F.A. , Kayser Matthew S.
Published: September 2024

Idiopathic hypersomnia (IH) is a poorly-understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role forbeat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophilabeat-Iaresults in sleepy flies and loss of the vertebrate ortholog ofbeat-Ia,CADM2, results in sleepy fish. We delineate a developmental function forbeat-Iain synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lackingCADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia.
Elucidating the role of multiple feedback loops in regulating stem cell decisions
Authors: Shaikh Razeen , Reeves Gregory T.
Published: September 2024

Stem cell decisions are regulated by a complex network of gene regulatory pathways that determine the reproductive health of the tissue. TheDrosophilaovarian germline is a well-characterized model system which facilitates visualizing stem cell behavior in its native environment to attain a systems-level understanding of the stem cell dynamics. The asymmetric division of the Germline Stem Cells (GSCs) forms two daughter cells–a self-renewed GSC and a differentiated Cystoblast (CB). The highly conserved Bone Morphogenetic Protein (BMP) pathway ensures growth and maintenance of the GSCs, but is downregulated in the CBs, to allow for differentiation. BMP signal transduction upregulatesdadand represses Fused, both of which are negative regulators of the BMP pathway. Moreover, these regulatory mechanisms operate on a system of two cells which remain connected during a portion of the cell cycle. We developed a biologically-informed mathematical model of multi-compartment GSC division to investigate the dynamic roles Dad and Fused play in determining cell fate. We found that Dad optimally controls the BMP signal transduction to enable GSC homeostasis and differentiation. IndadKOmutants, GSCs were more likely to divide symmetrically. Our work identifies the synergistic role of Dad and Fused rendering robustness to stem cell division.
Maximizing memory capacity in heterogeneous networks
Authors: Zhang Kaining , Tavoni Gaia
Published: September 2024

A central problem in neuroscience is identifying the features of neural networks that determine their memory capacity and assessing whether these features are optimized in the brain. In this study, we estimate the capacity of a general class of network models. Our derivation extends previous theoretical results, which assumed homogeneous connections and coding levels (i.e., activation rates of the neurons in memory patterns), to models with arbitrary architectures (varying constraints on the arrangement of connections between cells) and heterogeneous coding levels. Using our analytical results, we estimate the memory capacity of two types of brain-inspired networks: a general class of heterogeneous networks and a two-layer model simulating the CA3-Dentate Gyrus circuit in the hippocampus, known to be crucial for memory encoding. In the first case, we demonstrate that to maximize memory capacity, the number of inward connections and the coding levels of neurons must be correlated, presenting a normative prediction that is amenable to experimental testing. In the second case, we show that memory capacity is maximized when the connectivity and coding levels are consistent with the formation of memory “indices” in the Dentate Gyrus, which bind features in the CA3 layer. This suggests specific neural substrates for the hippocampal index theory of memory encoding and retrieval.
Ultra-Fast Multi-Organ Proteomics Unveils Tissue-Specific Mechanisms of Drug Efficacy and Toxicity
Authors: Xiong Yun , Tan Lin , Chan Wai-kin , Yin Eric S. , Donepudi Sri Ramya , Ding Jibin , Wei Bo , Tran Bao , Martinez Sara , Mahmud Iqbal , Stewart Hamish I. , Hermanson Daniel J. , Weinstein John N. , Lorenzi Philip L.
Published: September 2024

Rapid and comprehensive analysis of complex proteomes across large sample sets is vital for unlocking the potential of systems biology. We present UFP-MS, an ultra-fast mass spectrometry (MS) proteomics method that integrates narrow-window data-independent acquisition (nDIA) with short-gradient micro-flow chromatography, enabling profiling of >240 samples per day. This optimized MS approach identifies 6,201 and 7,466 human proteins with 1- and 2-min gradients, respectively. Our streamlined sample preparation workflow features high-throughput homogenization, adaptive focused acoustics (AFA)-assisted proteolysis, and Evotip-accelerated desalting, allowing for the processing of up to 96 tissue samples in 5 h. As a practical application, we analyzed 507 samples from 13 mouse tissues treated with the enzyme-drug L-asparaginase (ASNase) or its glutaminase-free Q59L mutant, generating a quantitative profile of 11,472 proteins following drug treatment. The MS results confirmed the impact of ASNase on amino acid metabolism in solid tissues. Further analysis revealed broad suppression of anticoagulants and cholesterol metabolism and uncovered numerous tissue-specific dysregulated pathways. In summary, the UFP-MS method greatly accelerates the generation of biological insights and clinically actionable hypotheses into tissue-specific vulnerabilities targeted by ASNase.
Ironing out the role of Nrf2 in cardiac iron metabolism during myocardial infarction
Authors: Jayakumar Deepthy , Narasimhan Kishore Kumar S. , Rajkumar Abinayaa , Panchalingam Gokul Prasanth , Chandrasekar Navvi , Ravikumar Varsha C. , Periandavan Kalaiselvi
Published: September 2024

Background and Purpose

Iron plays a crucial role in maintaining cardiac health. However, existing research has focused on understanding how cardiac cells regulates intercellular iron levels through their own cell-autonomous cardiac hepcidin/ferroportin axis. In Addition, several studies have explored the mechanisms linking cardiac dysfunction with iron imbalance. Recent insights also emphasize the importance of Nrf2, a key transcriptional regulator that not only counteracts iron-mediated oxidative stress, but also governs several genes involved in iron metabolism. Consequently, the Nrf2/hepcidin/ferroportin axis is emerging as a central hub connecting cardiac iron metabolism with redox alterations. However, the precise mechanisms linking these components remain elusive. This study aims to elucidate how disruptions in the Nrf2/hepcidin/ferroportin axis contribute to the altered iron metabolism in Myocardial infarction (MI).

Experimental Approach

MI was induced in adult Wistar rats by subcutaneous administration of isoproterenol (ISO; 85 mg/kg body weight) for two days. H9c2 cardiomyoblasts were differentiated into cardiomyocytes using all-trans-retinoic acid (ATRA, 2.5μM for 5-days) and subjected to hypoxic stress using CoCl2(100μM).In vitropharmacological suppression of Nrf2 was performed using brusatol (50nM).

Key Results

Morphological examination revealed maladaptive remodeling, and histopathological analysis demonstrated disoriented myofibrils with intense neutrophil infiltration and necrotic impressions in MI-affected animals. Furthermore, elevated levels of labile redox-active iron and inflammatory markers were observed in serum of ISO induced animals. qPCR & Western blot analysis indicated an increase in HIF-1α and hepcidin levels, and downregulation of FTH levels in MI-induced animals, with no significant changes observed in FPN-1. The transcriptional activity of Nrf2 is enhanced in the MI-heart. Moreover, increased levels of NCOA4, beclin-1, and LC3-II/LC3-I, along with decreased p62, suggest enhanced ferritinophagy in MI-induced hearts. Nrf2 was pharmacologically suppressed in differentiated H9c2 cardiomyocytes to explore its potential role in MI pathophysiology. Remarkably, this inhibition rescued CoCl2-induced hypoxic stress, as evidenced by the decreased ferritinophagy and apoptotic cell death.

Conclusion and Implications

Augmented Nrf2-transcriptional activity disrupts iron metabolism through the hepcidin/ferroportin axis, leading to iron sequestration and promoting ferritinophagy within cardiomyocytes, thereby exacerbating MI.
Polyunsaturated fatty acids and their endocannabinoid-related metabolites activity at human TRPV1 and TRPA1 ion channels expressed in HEK-293 cells
Authors: Abate Atnaf A , Santiago Marina J , Garcia-Bennett Alf , Connor Mark
Published: September 2024

Background

Polyunsaturated fatty acids (PUFAs), particularly Omega-3 (ω-3) and Omega-6 (ω-6) PUFAs, may exert neuroprotective effects via the endocannabinoid system (ECS) and are promoted as brain health supplements. However, despite their potential role in endocannabinoid biosynthesis, the impact of PUFAs on ion channels such as TRPV1 and TRPA1, which are modulated by endocannabinoids, remains incompletely understood. Furthermore, the potentialin vitroactions of ω-6 to ω-3 PUFA combined in the ratios available in supplements remains uncertain. Therefore, the objective of this study is to evaluate the functional activity of individual PUFAs, their combination in a specific ratio, and their endocannabinoid-related derivatives on TRPV1 and TRPA1 ion channels.

Methodology

We employed a fluorescent Ca-sensitive dye in HEK-293 Flp-In T-REx cells expressing human TRPV1, TRPA1, or an empty vector to measure changes in intracellular calcium concentration ([Ca2+]i).

Results

Capsaicin and certain PUFA derivatives such as DHEA, γ-LEA and AEA stimulate TRPV1 activity directly, whereas EPA, DHA, γ-LA, and their 9:3:1 ratio triggered TRPV1 response via a mechanism dependent on prior exposure to phorbol ester. Similarly, cinnamaldehyde and selected PUFA derivatives such as EPEA, DHEA, γ-LEA, 2-AG, 2-AG ether and AEA triggered TRPA1 response, with EPA, DHA, γ-LA, and the 9:3:1 ratio showing significant effects at higher concentrations.

Conclusions

PUFAs alone and their combined form in 9:3:1 ratio stimulate TRPA1 activity, whereas their metabolites trigger both TRPV1 and TRPA1 response. These findings suggest new avenues to explore for research into potential mechanisms underlying the neurological benefits of PUFAs and their metabolites.
Skeletal Metastasis of Prostate Cancer Is Augmented by Activation of EphA2 Noncanonical Signaling and Ligand-Deficient Bone Microenvironment
Authors: Lingerak Ryan , Petty Aaron , Shi Xiaojun , Kim Soyeon , Lin Hebei , Hsieh Jer-Tsong , Tang Dean , Stiles Bangyan , Wald David , Varambally Sooryanarayana , Chinnaiyan Arul M. , Lee Zhenghong , Morrissey Colm , Wang Bingcheng
Published: September 2024

EphA2, a member of Eph family receptor tyrosine kinases (RTKs), is overexpressed in multiple types of solid human tumors, particularly at the late stages. However, whether and how it drives specific malignant processes remain elusive. We report that EphA2 is elevated during prostate cancer (PCa) progression in multiple syngeneic murine models. Interestingly, human metastatic PCa specimens from two Rapid Autopsy Programs showed selective overexpression of EphA2 in metastasis to the bone, but not to the lymph nodes or viscera. Serine 897 phosphorylation that mediates the pro-oncogenic, noncanonical signaling by EphA2 was also upregulated in bone metastasis. Analysis of human datasets shows EphA2 overexpression is associated with skeletal but not visceral metastases. Ephrin-A1, a major cognate ligand for EphA2, is lost in PCa bone metastasis, which is correlated with poor prognosis. Further, the bone microenvironment is unique in expressing little of the fiveEFNAgenes, providing permissive microenvironment for bone colonization. S897A mutation that ablates EphA2 noncanonical signaling, suppressed PCa development. Restoration of ephrin-A1 expression in PC-3, a model cell line for double negative prostate cancer derived from bone metastasis and devoid of ephrin-As, profoundly changed global tyrosine phosphorylation profiles, inhibited basal ERK and Src activities in vitro, and suppressed tumor development in the bone. Together these results demonstrate EphA2 overexpression and concomitant loss of ligands in PCa lead to activation of noncanonical signaling that is sustained in ephrin-A1-deficient skeletal milieu to promote bone metastasis.
Loss-of-function of RNA-binding protein PRRC2B causes translational defects and congenital cardiovascular malformation
Authors: Das Debojyoti , Khor Eng-Soon , Jiang Feng , He Jiali , Kawakami Yui , Wainwright Lindsey , Hollinger Jared , Geiger Joshua , Liu Huan , Meng Fanju , Porter George A. , Jin Zhenggen , Murphy Patrick , Yao Peng
Published: September 2024

Alternative splicing generates variant forms of proteins for a given gene and accounts for functional redundancy or diversification. A novel RNA-binding protein,Pro-richCoiled-coil Containing Protein2B(PRRC2B), has been reported by multiple laboratories to mediate uORF-dependent and independent regulation of translation initiation required for cell cycle progression and proliferation. We identified two alternative spliced isoforms in human and mouse hearts and HEK293T cells, full-length (FL) and exon 16-excluded isoform ΔE16. A congenital heart disease-associated human mutation-mimicry knock-in of the equivalent variant in the mouse genome leads to the depletion of the full-lengthPrrc2bmRNA but not the alternative spliced truncated form ΔE16, does not cause any apparent structural or functional disorders. In contrast, global genetic inactivation of the PRRC2B gene in the mouse genome, nullifying both mRNA isoforms, caused patent ductus arteriosus (PDA) and neonatal lethality in mice. Bulk and single nucleus transcriptome profiling analyses of embryonic mouse hearts demonstrated a significant overall downregulation of multiple smooth muscle-specific genes inPrrc2bmutant mice resulting from reduced smooth muscle cell number. Integrated analysis of proteomic changes inPrrc2bnull mouse embryonic hearts and polysome-seq and RNA-seq multi-omics analysis in human HEK293T cells uncover conserved PRRC2B-regulated target mRNAs that encode essential factors required for cardiac and vascular development. Our findings reveal the connection between alternative splicing regulation of PRRC2B, PRRC2B-mediated translational control, and congenital cardiovascular development and disorder. This study may shed light on the significance of PRRC2B in human cardiovascular disease diagnosis and treatment.

Discovery bullet points

PRRC2B has two alternative splicing isoforms, full-length and exon 16-skipped (ΔE16) mRNAs in humans and mice.

Full-lengthPrrc2bKO mice show no apparent cardiac phenotypes, while double KO of full-length and ΔE16 causes patent ductus arteriosus and neonatal lethality in mice.

Multi-omics analyses ofPrrc2bdouble KO mice suggest changes in SMC cell abundance and dysregulation of translation of specific proteins in E18.5 embryos.

CRISPR-Cas9-mediated KO ofPRRC2Bin human cells reduces the translation of heart and valve development-related mRNAs.
Synergizing Health Strategies: Exploring the Interplay of Treatment and Vaccination in an Age-Structured Malaria Model
Authors: Hridoy Mahmudul Bari , Peace Angela
Published: September 2024

Malaria remains a persistent global challenge, particularly prevalent in tropical regions of Africa, Asia, and South America. According to the World Health Organization’s (WHO) World Malaria Report 2023, there were approximately 249 million reported malaria cases in 2022 across 85 endemic countries, resulting in over half a million deaths. Progress towards global malaria eradication through antimalarial drugs has been slow, with case numbers increasing since 2015. Dihydroartemisinin (DHA), artesunate, and artemether, derivatives of artemisinin, are crucial components of modern antimalarial treatment. However, resistance to these drugs and their partners in Artemisinin Combination Therapy (ACT) has emerged in Southeast Asia, Africa, and South America. In 2021, the WHO recommended widespread use of the RTS,S malaria vaccine among children in endemic regions. To address these challenges, we develop an extended SEIR age-structured model incorporating malaria vaccination for children, drug-sensitive and drug-resistant strains, and interactions between human hosts and mosquitoes. Our research focuses on evaluating how malaria vaccination coverage influences disease prevalence and transmission dynamics. We derive the basic, intervention, and invasion reproduction numbers for both strains and conduct sensitivity analysis to identify key parameters affecting infection prevalence. Our findings reveal that model outcomes are primarily influenced by scale factors that reduce transmission and natural recovery rates for the resistant strain, as well as by drug treatment and vaccination efficacies, and mosquito death rates. Numerical simulations indicate that while treatment reduces the malaria disease burden, it also increases the proportion of drug-resistant cases. Conversely, higher vaccination efficacy correlates with lower infection cases for both strains. These results suggest that a synergistic approach, involving both vaccination and treatment, could effectively decrease the overall proportion of the population that is infected.
Maternal Diet Quality and BMI as Predictors of Human Milk Composition and Exclusive Breastfeeding Duration
Authors: Cetinkaya Hatice , Valentine Christina J. , Dingess Kelly A. , Ollberding Nicholas J. , Summer Suzanne S. , Meredith Nathan A. , Maria Sarah D. , Morrow Ardythe L. , Nommsen-Rivers Laurie A.
Published: September 2024

Background

Poor diet quality and high body mass index (BMI) contribute to inflammation, which may influence human milk composition and exclusive breastfeeding (EBF) duration.

Objective

We evaluated maternal diet and prepregnancy BMI as predictors of human milk C-reactive protein (CRP) and long chain fatty acid concentrations (%LCFA), and EBF duration.

Methods

We utilized the Global Exploration of Human Milk Study-Cincinnati subset (n=114), where healthy dyads continued follow-up if ≥75% of feeds were breastmilk at 4 weeks postpartum. We computed a Dietary Inflammatory Index (DII) from diet recalls obtained between 4-13 weeks postpartum, where higher score indicates a more proinflammatory diet. Milk CRP and fatty acid analyses were performed on week 4 milk. We compared milk CRP across 4 combinations of DII×BMI using the Kruskal Wallis test, with BMI categorized as normal versus elevated (<25 versus>25 kg/m2), and DII split at the median. Linear regression was used to examine DII and BMI as predictors of %LCFA. Logistic regression was used to examine DII tertiles and BMI as predictors of EBF duration.

Results

Milk CRP concentrations differed across DII×BMI groups (p=0.009): the low DII/normal BMI group had the lowest milk CRP (n=30, median [Q1, Q3], 64.3 [38.2, 121.4] ng/mL) versus all other groups (n=70, 124.1 [71.2, 181] ng/mL,p=0.022). Lower milk %LCFA was predicted by higher DII score (β±SE = -0.68 ± 0.21,p=0.002, n=103) and higher BMI (β±SE = -0.13 ± 0.01,p=0.043, n=114). Having the highest DII tertile and elevated BMI lowered the odds of EBF at week 6 (OR [95% CI]: 0.26 [0.07, 0.85]) compared to the referent group (low or medium DII, normal BMI).

Conclusions

Milk CRP concentrations were lowest in women with a more anti-inflammatory diet and normal BMI. Both higher BMI and proinflammatory diet predict lower milk %LCFA and lower EBF prevalence at week 6.
Domain specific Memory Impairments in Bipolar Mania: Insights from a Tertiary Care Study
Authors: Kumar Mohit , Kumar Sanjay , Khusboo  , Maqbool Masood , Singh Vinit Kumar , Soni Amit Kumar
Published: September 2024

Background

Cognitive deficits in bipolar affective disorder (BPAD), particularly during manic episodes, are well-documented. However, research on domain-specific memory impairments in bipolar mania is limited, especially in the Indian subcontinent. This study aimed to assess memory impairments in patients with bipolar mania using the Postgraduate Institute Memory (PGI-Memory) Scale and to highlight domain-specific deficits compared to healthy controls.

Methods

This cross-sectional study was conducted at Tertiary Care Centre in North India. Twenty patients diagnosed with bipolar mania and twenty age, sex and education-matched healthy controls between age 18 to 40 were recruited. Memory functions were assessed using the PGI-Memory scale, focusing on immediate, recent, remote, long-term memory, and associative memory. Mental control and working memory were also evaluated.

Results

Both groups were matched in terms of age, sex, and education. the mean (sd) age for bipolar mania group was 27.2 (4.14) years. Patients with bipolar mania demonstrated significant deficits in various memory domains, including immediate, recent, remote, long-term, and associative memory, as well as in visual reproduction and recognition tasks. In contrast, their working memory performance was comparable to that of the control group. The largest deficits were observed in long-term memory (d =2.37) and visual reproduction (d=2.30).

Conclusions

Bipolar mania is associated with widespread memory impairments, particularly in long-term and associative memory, which may contribute to difficulties in emotional regulation and daily functioning. These findings emphasize the importance of considering memory impairments in the diagnosis and management of BPAD. Further studies are required to investigate the neurobiological foundations of these impairments and to develop specific interventions.
Integrating health care and early years support for children and young people living in deprivation: A cost effectiveness analysis of a novel integrated clinic in Birmingham, UK
Authors: Melyda Melyda , Monahan Mark , Bird Chris , Roberts Tracy , Harper Lorraine , Litchfield Ian
Published: September 2024

Background

Increased use of emergency and secondary care by children and young people, especially in deprived populations, drive increased costs in health and social care systems in rich country settings, without necessarily delivering quality care.

Aim

To assess the potential cost-effectiveness of the Sparkbrook’s Children Zone (SCZ), a pilot clinic for children and young people which integrates health and early years support in a highly deprived area of Birmingham, the UK’s second city, compared with standard primary care.

Methods

A decision-analytic model taking healthcare and partial social care perspective was developed using best available, though limited, evidence from aggregated data of an ongoing pilot, published literature, expert opinions and assumptions. Effectiveness was measured as proportion of patients attending the emergency department. Deterministic and probabilistic sensitivity analyses were performed to assess the impact of parameter uncertainties.

Results

The integrated SCZ clinic may potentially be cost-effective based on this preliminary model-based analysis. The SCZ had lower proportion of patients attending emergency department, 0.017 compared with 0.029 for standard primary care, reducing proportion of emergency department visits by 0.012. The average cost of SCZ was £66.22 compared with £110.36 for standard primary care, leading to a cost-saving of £44.08 per patient. This potential reduction in total costs resulting from fewer referrals to children’s social care and secondary medical services, including the emergency department. Extensive sensitivity analysis supported the indications that the intervention was likely to be cost-effective.

Conclusion

The SCZ pilot shows potential in integrating health and social care within a community setting, with Its early years services likely enhancing the cost-effectiveness of the SCZ compared to standard primary care. Further robust data and trial evaluation are essential to confirm these findings, ensuring the scalability and sustainability of such programs.
Neighborhood deadwood and yard rewilding modulate commensal microbiota and inflammatory signals among urbanites
Authors: Roslund Marja I. , Uimonen Laura , Kummola Laura , Cerrone Damiano , Ojala Ann , Luukkonen Anna , Holopainen Ella , Korhonen Aku , Penttilä Reijo , Venäläinen Martti , Haveri Hanna , Rajaniemi Juho , Laitinen Olli H. , Sinkkonen Aki ,   the BIWE research group
Published: September 2024

Background

Global ecosystem deprivation is linked to reduced microbial diversity and diminished immunological resilience. Urban rewilding and decomposing plant matter have been suggested to reverse this deprivation and support human health.

Methods

We rewilded 21 urban private yards with vegetation and deadwood. Control yards (15) were analyzed for comparison. We collected microbial samples and used vegetation and deadwood inventories, landcover data and questionnaires to determine the effects of rewilding and living environment on skin and salivary microbiota, gene pathways and cytokine levels (IL-6, IL-10). Samples were collected before the rewilding in summer and three months later in autumn.

Findings

Rewilding preserved skin microbial richness in comparison to control group, including previously health-associated Alpha- and Gammaproteobacteria, despite the normal seasonal decline and less outdoor time in autumn. Deadwood abundance within 200-m radii associated directly to beta diversity of skin microbiota and Gammaproteobacterial taxonomies.

In saliva, deadwood was directly associated with the diversity of functional gene pathways, which in turn was negatively associated with pleiotropic IL-6 levels. Rewilding was associated with a decrease in L-histidine degradation and an increase in Mycobacteriaceae.

Interpretation

Since both yard rewilding and neighborhood deadwood preserved rich commensal microbiota and reduced pro-inflammatory signals, decomposing plant matter, not just plant richness, seems to be crucial for ecosystem services that contribute to health. Since deadwood abundance was associated to reduced pro-inflammatory signals, it may be a suitable indicator of environment supporting immunological resilience.

Our findings provide an incentive for future strategic investments for planetary health.

Funding

Strategic Research council Finland.
Predicting Common Pathway Signatures Between DNA Methylation and Post Translational Modification in Type II Diabetes & Parkinson’s Disease Using Heterogeneous Data Integration
Authors: Biswas First Saikat , Mitra Second Pabitra , Rao Third Krothapalli Sreenivasa
Published: September 2024

The complex diseases, namely, Type 2 Diabetes Mellitus (T2DM) and Parkinson’s Disease (PD), are extensively studied due to their prevalence in a large population group. Between these two diseases, T2DM is denoted as the zero index disease in a patient, which may lead to PD in a more advanced clinical stage. Both of these diseases may occur due to abrupt DNA methylation of genes. Likewise, both diseases may occur in a patient due to protein misfolding. Our study proposes a novel framework for building two disease-specific heterogeneous networks by integrating different tissue-based transcriptomics, epigenetics, epistasis, and PPI-based topological information. We predict the missing links between the DNA methylation and Post-Translational Modification (PTMs) associated with protein aggregation. Next, we have predicted the common signature of the prevalence of linked patterns in both diseases, further validated by relevant biological evidence.
Leveraging Pretrained Vision Transformers for Automated Cancer Diagnosis in Optical Coherence Tomography Images
Authors: Ray Soumyajit , Lee Cheng-Yu , Park Hyeon-Cheol , Nauen David W. , Bettegowda Chetan , Li Xingde , Chellappa Rama
Published: September 2024

This study presents a novel approach to brain cancer detection based on Optical Coherence Tomography (OCT) images and advanced machine learning techniques. The research addresses the critical need for accurate, real-time differentiation between cancerous and noncancerous brain tissue during neurosurgical procedures. The proposed method combines a pre-trained Vision Transformer (ViT) model, specifically DiNOV2, with a convolutional neural network (CNN) operating on Grey Level Co-occurrence Matrix (GLCM) texture features. This dual-path architecture leverages both the global context capture capabilities of transformers and the local texture analysis strengths of GLCM + CNNs. The dataset comprised OCT images from 11 patients, with 5,831 B-frame slices used for training and validation, and 1,610 slices for testing. The model achieved high accuracy in distinguishing cancerous from noncancerous tissue, with 99.7% ± 0.1% accuracy on the training dataset, 99.4% ± 0.1% on the validation dataset and 94.9% accuracy on the test dataset. This approach demonstrates significant potential for achieving and improving intraoperative decision-making in brain cancer surgeries, offering real-time, high-accuracy tissue classification and surgical guidance.
Multi-omics integration prioritizes potential drug targets for multiple sclerosis
Authors: Jiang Yuan , Liu Qianwen , Stridh Pernilla , Kockum Ingrid , Olsson Tomas , Alfredsson Lars , Diaz-Gallo Lina Marcela , Jiang Xia
Published: September 2024

Background and Objectives

Multiple sclerosis (MS) is a chronic autoimmune disease with limited treatment options. Thus, drug discovery and repurposing are essential to enhance treatment efficacy and safety.

Methods

We obtained summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma proteins and 1,443 brain proteins, a genome-wide association study (GWAS) of MS susceptibility with 14,802 cases and 26,703 controls, and expression quantitative trait loci (eQTL) for 8,000 genes in peripheral blood and 16,704 genes in brain tissue. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization (SMR) to determine causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing SMR, HEIDI, and colocalization analyses were considered potential drug targets. We further conducted pathway annotations, protein-protein interaction (PPI) network analysis, and examined mRNA levels of these targets.

Results

We identified hundreds of MS-associated proteins in plasma and brain, confirming the causal roles of 18 proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also discovered intricate PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. Combining expression data, we identified two targets adhering to the central dogma of molecular biology.

Discussion

We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for drug discovery and repurposing in MS.
Bidirectional genetic and phenotypic links between smoking and striatal iron content involving dopaminergic and inflammatory pathways
Authors: Trofimova Olga , Iuliani Ilaria , Bergmann Sven
Published: September 2024

Tobacco smoking is a major modifiable risk factor for cardiovascular and lung diseases. A better understanding of its neurobiological underpinnings will benefit the prevention of smoking-related illnesses and mortality. Recent neuroimaging studies have identified a correlation between smoking and iron concentration in the brain’s striatum, a subcortical region involved in habit formation and compulsive behaviour, and a central node of dopamine activity. Moreover, iron accumulation in the striatum is associated with lower cognitive performance in adults. Here, we investigated phenotypic and genetic correlations, and causal relationships between smoking initiation (ever smoked regularly) and susceptibility-weighted magnetic resonance imaging (MRI)-derived markers of iron content–T2* and quantitative susceptibility mapping (QSM)–in the bilateral putamen, caudate, and accumbens nuclei. We computed correlations between smoking and striatal iron in the UK Biobank, adjusting for a vast set of imaging and non-imaging confounders. Using genome-wide association studies (GWAS) summary statistics, we performed global genetic correlation, cross-GWAS coherence tests at the gene level, and causality analysis using Mendelian randomisation and PascalX. Smoking was positively correlated with iron content in the bilateral putamen, caudate, and in the left accumbens, with the strongest effect found when contrasting current and never smokers. Striatal iron had a positive association with pack-years and a negative relationship with years since stopping smoking, indicating a possible reversal of iron accumulation after smoking cessation. Genetic correlation paralleled phenotypic correlation. Cross-GWAS signal was coherent in genes involved in the dopaminergic and glutamatergic systems, and synaptic function. There was evidence of a causal relationship from smoking to striatal iron through genes involved in synaptogenesis and plasticity, and to a lesser extent, from striatal iron to smoking through inflammatory and immune system related genes. Moreover, the heterogeneity of genes with correlated and anti-correlated signals suggests that the neurobiological mechanisms linking iron to smoking behaviour are highly complex. Overall our results show an association between cigarette smoking and iron concentration in the striatum with complex multi-directional causal mechanisms involving synaptic transmission and inflammatory circuits.
Longitudinal Changes in Lifestyle Behaviors and Cardiovascular Health During the Transition to Fatherhood: The Dad Bod Study Rationale and Design
Authors: Landry Matthew J. , Pineda Jocelyn P. , Lee Jaylen M. , Hoyt Michael A. , Edwards Karen L. , Lindsay Karen L. , Gardner Christopher D. , Wong Nathan D.
Published: September 2024

Background

Despite the importance of the transition to fatherhood as a critical life stage among young adult men, much remains unknown about the factors predictive of ideal cardiovascular health (CVH) and how CVH is impacted as young men face new roles and responsibilities associated with fatherhood.

Methods

To address this gap, the Dad Bod Study is a prospective, longitudinal and observational study designed to examine how fatherhood affects young men’s CVH. A total of 125, first-time prospective fathers (men, 19-39 years) will be enrolled and followed over 1.5 years. Metrics of the American Heart Association’s “Life’s Essential 8” as well as demographic, social, and psychosocial factors will be collected at four time points ((baseline (during the pregnant partner’s 2nd trimester) 1-month postpartum, 6-months postpartum, and 1-year postpartum). The primary aims are to measure predictors of CVH among first-time fathers and describe longitudinal changes in CVH. A secondary aim is to identify best practices for recruitment, retention, and remote data collection in this population.

The Dad Bod Study offers a novel examination of CVH among first-time fathers, exploring how new paternal roles and responsibilities impact cardiovascular health. Findings may provide key insights into critical CVH behaviors and risk factors to monitor, preserve, and improve as young men transition to fatherhood.
Human NK cell responses to the SARS-CoV-2 Spike269-277peptide YLQPRTFLL
Authors: Bilev Eleni , Schiele Simone , Foglietta Beatrice , Ljunggren Hans-Gustaf , Hammer Quirin
Published: September 2024

Natural killer (NK) cells act as the first line of defense against virus infections. The effector functions of human NK cells are controlled by inhibitory and activating receptors, including NKG2A and NKG2C, which recognize peptides presented by HLA-E. Recent studies have suggested that the SARS-CoV-2 Spike269-277peptide YLQPRTFLL may modulate NK cell activity. Here, we show that the YLQPRTFLL peptide is poorly presented by HLA-E. Functional interrogation further revealed that loading of target cells with YLQPRTFLL did not affect the effector functions of NKG2A+nor NKG2C+NK cells. Our findings thus indicate that the Spike269-277peptide YLQPRTFLL has a limited influence on human NK cell responses.
The translation inhibitors kasugamycin, edeine and GE81112 target distinct steps during 30S initiation complex formation
Authors: Safdari Haaris A. , Morici Martino , Sanchez-Castro Ana , Dallapè Andrea , Paternoga Helge , Giuliodori Anna Maria , Fabbretti Attilio , Milón Pohl , Wilson Daniel N.
Published: September 2024

During bacterial translation initiation, the 30S ribosomal subunit, initiation factors, and initiator tRNA define the reading frame of the mRNA. This process is inhibited by kasugamycin, edeine and GE81112, however, their mechanisms of action have not been fully elucidated. Here we present cryo-electron microscopy structures of 30S initiation intermediate complexes formed in the presence of kasugamycin, edeine and GE81112 at resolutions of 2.0-2.9 Å. The structures reveal that all three antibiotics bind within the E-site of the 30S and preclude 30S initiation complex formation. While kasugamycin and edeine affect early steps of 30S pre-initiation complex formation, GE81112 stalls pre-initiation complex formation at a further step by allowing start codon recognition, but impeding IF3 departure. Collectively, our work highlights how chemically distinct compounds binding at a conserved site on the 30S can interfere with translation initiation in unique manner.
Protocol for simultaneous evaluation of neuronal activity and neurotransmitter release following chronic amyloid-beta oligomer injections into the hippocampus
Authors: Hervé Vincent , Bonenfant Laurie , Amyot Mathilde , Balafrej Rime , Ali Obai Bin Ka’B , Benali Habib , Brouillette Jonathan
Published: September 2024

In Alzheimer’s disease, there is an imbalance in neurotransmitter release and altered neuronal activation. We present a novel approach to analyze neuronal activity by combining local field potential (LFP) recording with microdialysis within the same animal. This method measures glutamate and GABA levels following chronic hippocampal amyloid-beta oligomer (Aβo) injections in rats. We outline the design of our electrode and canula, the surgical procedure, and the steps for LFP recording, interstitial fluid collection, and Aβo injections simultaneously in living animal.

Graphical abstract
Minimizing the number of phosphenes required for object recognition under prosthetic vision
Authors: Scialom Elsa , Ernst Udo A. , Rotermund David , Herzog Michael H.
Published: September 2024

Cortical prostheses offer the potential for partial vision restoration in individuals with blindness by stimulating V1 neurons to produce phosphenes. However, the low number of phosphenes that can be elicited in practice makes encoding of whole objects difficult, and the round shape of phosphenes lack the contour cues necessary for perceptual grouping. We propose a minimalistic encoding approach that focuses on essential visual information. We fragmented objects’ contours into either phosphenes or curved segments, providing either low or high local visual information. 46 participants identified these fragmented objects in a free-naming task. The number of fragments gradually increased to quantify the minimum number of phosphenes and segments necessary to recognize objects. Most objects could be recognized with only 65 phosphenes, which is in the range of implantable electrodes in human patients. Participants required 27% fewer segments than phosphenes to recognize objects. Including individual objects as a random effect in a linear mixed model substantially increased the explained variance, suggesting that the minimal number of fragments required for object recognition in prosthetic vision strongly depends on the particular object. Our results demonstrate that a minimalistic approach can substantially reduce the number of phosphenes required for recognition, emphasizing the importance of identifying critical object features to minimize brain stimulation in visual prostheses.
“Regressing Away Common Neural Choice Signals does not make them Artifacts. Comment on Frömer et al (2024, Nature Human Behaviour)”
Authors: O’Connell Redmond G. , Corbett Elaine A. , Parés-Pujolràs Elisabeth , Feuerriegel Daniel , Kelly Simon P.
Published: September 2024

Frömer et al (2024, Nature Human Behaviour) apply a deconvolution method to correct for component overlap in the event-related potential. They report that this method eliminates signatures of sensory evidence accumulation from response-aligned measurements of the centro-parietal positivity (CPP), suggesting that these signatures arise artifactually.. Here, we argue that the analysis and interpretation of their perceptual choice data are critically flawed. We demonstrate with simulations that the deconvolution analyses used by the authors are not designed to reliably test for the presence or absence of bounded accumulation signals.
Undoing of firing rate adaptation enables invariant population codes
Authors: Brandão Sofia C. , Ramirez Luisa , Walter Alexander M , Silies Marion , Martelli Carlotta
Published: September 2024

Adaptation often implements an efficient coding strategy to align neuron sensitivity to relevant stimuli. However, when sensory information is encoded in populations of neurons, adaptation of individual units could deteriorate stimulus information relevant for behavior. One prominent example is the encoding of olfactory information, which occurs at the population level. We show that if individual ORNs were to adapt following an efficient coding principle, contrast information would be lost at the population level, impairing the detection of ON and OFF stimuli. Surprisingly, adaptation of ORN firing responses is compensated at the axon terminal, where calcium transients are kept background-invariant by inhibitory feedback. We demonstrate that achieving this invariance across different background conditions requires an adaptation strategy that shifts response amplitude, rather than sensitivity as predicted by the efficient coding principle. This background invariance is passed on to second-order olfactory neurons, through facilitation of vesicle release that involves modulation of Unc13 proteins. We conclude that synaptic and circuit computations compensate peripheral firing rate adaptation, enhancing the separation of ON and OFF contrasts, while preserving the identity of ON stimuli in population codes. Our findings identify a strategy that allows neural circuits to minimize the cost of information transmission while preserving information content.
MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression
Authors: Hofstätter Azambuja Juliana , Yerneni Saigopalakrishna S. , Maurer Lisa M. , Crentsil Hannah E. , Debom Gabriela N. , Klei Linda , Smyers Mei , Sneiderman Chaim T. , Schwab Kristina E. , Acharya Rajesh , Lin Wu Yijen , Ekambaram Prasanna , Hu Dong , Gough Pete J. , Bertin John , Melnick Ari , Kohanbash Gary , Bao Riyue , Lucas Peter C. , McAllister-Lucas Linda M.
Published: September 2024

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage “M1-like” phenotype. Preclinicalin vivoanalysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM.

Graphical abstract.

The effects of tumor cell-induced CARD9-BCL10-MALT1 (CBM) activation (left) and MALT1 protease inhibition (right) on GBM associated macrophages in the tumor microenvironment.

Cartoon of cellular components of a GBM tumor with an immunosuppressive TME characterized by “M2-like macrophages” (left) and conversion to a more immune-reactive tumor microenvironment characterized by “M1-like macrophages and increased effector T-cells (right) as a result of MALT1 protease inhibition.