bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Strategies for Autologous Fat Grafting in Breast Augmentation and Reconstruction: A Systematic Review and Network Meta-Analysis
Authors: Sun Yulin , Liu Qian , Zhu Jie , Hu Hao , Lu Lu , Ying Jianghui , Guo Rong , Ye Xiuyu , Zhu Lie , Jiang Hua
Published: July 2024

Background:

Cell-assisted lipotransfer (CAL) and platelet-rich plasma (PRP)–assisted lipotransfer have been used to overcome the low survival rate of conventional lipotransfer. However, there is still insufficient evidence to determine which technique is the best strategy for autologous fat grafting in breast cosmetic and reconstructive surgery. The present study aimed to compare the efficacy of traditional fat transplantation, CAL, and PRP-assisted lipotransfer.

Methods:

A systematic search was conducted in several databases, including PubMed, Web of Science, Cochrane, ClinicalTrials.gov, and Embase, concluding on January 21, 2024, to identify studies that met the inclusion criteria. Twelve studies were included after a rigorous selection process based on predefined criteria. Statistical analyses were conducted using R version 4.0.5 software with the netmeta and dmetar packages, utilizing a frequentist approach with a random-effects model. A network meta-analysis was performed to compare different fat graft procedures with regard to fat survival rate and complication events.

Results:

CAL and PRP-assisted lipotransfer were better than traditional fat grafting in terms of fat survival rate. In addition, there was no significant difference in the incidence of postoperative complications among the CAL, PRP, and traditional groups.

Conclusions:

Given the results of network meta-analysis, it appears that both CAL and PRP-assisted lipotransfer have a higher fat survival rate for autologous fat grafting in breast augmentation and reconstruction. However, the transplantation strategy still needs to be analyzed based on actual conditions in clinical applications.
Study of Genetic Mutations and Their Association With the Development of Atopic Dermatitis and Other Skin Diseases
Authors: Hartmane Ilona
Published: July 2024

The purpose of this study was to identify the heterogeneity of atopic dermatitis and to identify key genetic factors. This can lead to new approaches and personalized treatment strategies. I conducted a literature review of three scientific publication platforms (i.e., PubMed, Cochrane Library, Scopus) for records published between July 2011 and July 2023 using key words related to the genetics of atopic dermatitis. The high heritability and genetic pleiotropia of atopic dermatitis emphasize the importance of its genetic predisposition and interaction with concomitant diseases. The study also shows the role of various genes associated with immunity and inflammatory reactions, as well as the high heritability of atopic dermatitis, particularly among twins. Genetic mutations, specifically polymorphisms of genes encoding immune factors and inflammatory responses, determine an individual’s predisposition to atopic dermatitis. Research findings also point to genetic aspects associated with other skin conditions such as psoriasis and vitiligo, confirming the existence of common genetic mechanisms between these diseases. Specifically, polymorphisms of the filaggrin gene have been found to be key genetic determinants of atopic dermatitis. I analyzed the genetic basis of atopic dermatitis, emphasizing the importance of genetic determinants and their interaction with the immune system and extracellular matrix. This study contributes to the understanding of the mechanisms of atopic dermatitis and opens new perspectives for individualized treatments.
Using an Innovative Protective Sleeve to Reduce Skin Compression Complications in Axillary Osmidrosis Surgery
Authors: Ho Benjamin Xi En , Ho Wen-Tsao
Published: July 2024

Osmidrosis is a condition characterized by malodorous sweat production in the armpits that often necessitates surgical intervention with tie-over bandages in the axillary area. Standard tie-over bandages may cause skin compression-related complications, such as bruising and skin erosion. To address this issue, we developed a novel technique using a modified protective sleeve.

We conducted an observational study involving 60 patients undergoing axillary osmidrosis surgery and divided them into groups. In the experimental group we used a novel technique that included using a modified protective sleeve secured with 4-0 silk sutures. In the control group we used standard tie-over bandages. We created the protective sleeve from the tail of a 3 mL syringe by drilling holes on both sides and securing it onto a 10 mm-wide Penrose drain. We threaded sutures through the holes and provided padding between the sutures and the skin. We assessed primary outcomes of bruising and skin breakdown at eight anchoring sites. We found that using the novel protective sleeve significantly reduced skin complications. Compared with standard bandages, the incidence of bruising was reduced by 83.33% (i.e., 16.7% vs 70%). The incidence of skin erosion was reduced by 75% (10% vs 40%). Notably, the control group exhibited delayed complications, such as hypertrophic scars.
Analysis of Factors Determining Spleen Preservation during Laparoscopic Distal Pancreatectomy – A Cohort Study
Authors: Borys Maciej , Wysocki Michał , Gałązka Krystyna , Budzyński Andrzej
Published: July 2024

Background:

Spleen preservation during laparoscopic distal pancreatectomy (LSPDP) should be pursued if safe and oncologically justified. The aim of the presented study was to compare surgical outcomes and identify risk factors for unplanned splenectomy during laparoscopic distal pancreatectomy and evaluate short and long-terms outcomes.

Methods:

The following study is a retrospective cohort study of consecutive patients who underwent laparoscopic distal pancreatectomy, with the intention of preserving the spleen, for benign tumors of the body and tail of the pancreas between August 2012 and December 2022. Follow-up for patients’ survival was completed in January 2023. In all, 106 patients were in total included in this study. Median age was 58 (41 to 67) years. The study population included 29 males (27.4%) and 77 females (72.6%).

Results:

Spleen preservation was possible in 67 (63.2%) patients. The tumor size was larger in the splenectomy group (respectively, 30 (16.5 to 49) vs. 15 (11 to 25); P<0.001). Overall, serious postoperative morbidity was 13.4% in the LSPDP group and 20.5% in the second group (P=0.494). There were no perioperative deaths. The postoperative pancreatic fistula rate was 18% in the splenectomy group and 14.9% in the LSPDP group, while B and C fistulas were diagnosed in 15.4% and 10.5% of patients, respectively. In the multivariate logistic regression model, tumor size >3 cm was found to independently increase odds for unplanned splenectomy (OR 8.41, 95%CI 2.89-24.46; standardized for BMI).

Conclusion:

Unplanned splenectomy during the attempt of LSPDP does not increase the risk for postoperative morbidity and postoperative pancreatic fistula. The independent risk factor for unplanned splenectomy during LSPDP is tumor size above 3 cm.
Enzymatic preparation and antioxidant activities of protein
hydrolysates from defatted egg yolk
Authors: Ko Go-Eun , Kwak Na-Yeong , Nam Ha-Eun , Seo Su-Jin , Lee Syng-Ook
Published: July 2024

This study aimed to investigate the characteristics of protein hydrolysates
derived from defatted egg yolk using various proteolytic enzymes and compare the
antioxidant activity of the resulting hydrolysates. The defatted egg yolk powder
was subjected to enzymatic hydrolysis using four different proteases (alcalase,
bromelain, flavourzyme and neutrase), and the resulting hydrolysates were
evaluated for their antioxidant properties. Through analysis of available amino
group contents and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, it
was observed that the defatted egg yolk powder treated with alcalase,
flavourzyme, and neutrase for 12 h exhibited a high degree of hydrolysis value.
Based on the RC50 values obtained from two different antioxidant
analyses, all hydrolysates showed comparable antioxidant activity, except for
the alcalase hydrolysate, which demonstrated notably higher scavenging activity
against hydrogen peroxide than the other hydrolysates. These findings suggest
the potential of protein hydrolysates from defatted egg yolk, a by-product of
lecithin extraction, as natural antioxidants.
Antioxidant activity and neuroprotective effect of ethanolic
extract of Polygonum multiflorum
Authors: Choi Hye Ji , Lee Hyo Lim , Go Min Ji , Kim Ju Hui , Lee Han Su , Kim In Young , Heo Ho Jin
Published: July 2024

This study evaluated the in vitro antioxidant activities of
ethanolic Polygonum multiflorum (P.
multiflorum) extracts and their cytoprotective effects on
H2O2-induced HT22 and SK-N-MC cells. Among ethanolic
extracts of P. multiflorum, the 40% ethanolic extract of
P. multiflorum exhibited high total phenolics and flavonoid
contents, with 105.68 mg of GAE/g and 28.92 mg of RE/g, respectively. The
40% ethanolic extract of P. multiflorum showed a high
2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt
(ABTS) radical scavenging activity and malondialdehyde (MDA) inhibitory effect.
The 40% ethanolic extract of P. multiflorum also showed
efficient inhibitory activity against α-glucosidase and
acetylcholinesterase. Moreover, the 40% ethanolic extract of P.
multiflorum reduced oxidative stress and increased cell viability
in H2O2-induced HT22 and SK-N-MC cells as determined by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zoliumbromide (MTT) and
2’,7’-dichlorodihydrofluorescein diacetate (DCF-DA) assay.
High-performance liquid chromatography (HPLC) identified
2,3,5,4’-tetrahydroxystilbene-2-Ο-beta-D-glucoside (TSG) as the bioactive
compound in the 40% ethanolic extract of P.
multiflorum.
Happiness promotes global processing in haptic perception
Authors: Cavdan Müge , Kapucu Aycan , Doerschner Katja , Drewing Knut
Published: July 2024

Happy and sad mood promote global and local visual processing, respectively. However, it is unclear whether mood also affects the processing level in haptic perception. Here, we used classical music to induce happy and sad mood in blindfolded participants before they scanned 3D-printed configurations with their fingers. Additionally, we included a neutral group who did not listen to any music. Global shapes were triangles, circles, or squares (33mm) composed of smaller local relief shapes (3 mm): either triangles, circles, or squares. Participants explored a probe stimulus with identical local and global shapes, and two comparison stimuli, matching the probe in local, or global shape. They reported which comparison stimulus appeared more similar to the probe. In the 'sad' group, participants chose the locally matching comparison more frequently than in the 'happy' and 'neutral' groups, revealing that sad mood promotes local processing also in touch. Overall, participants chose the globally matching comparison more often, suggesting that global processing is more prominent in touch than previously assumed.
Differences in drug intake levels (high versus low takers) do not necessarily imply distinct drug user types: insights from a new cluster-based model
Authors: Castaneda Diego Martinez , Job Martin O
Published: July 2024

Background

Classifying psychostimulant users as high and low responders based on median split of drug intake levels has face-validity: these appear to be different types of drug users. However, because psychostimulant intake levels a) are defined by an inverted U-shaped dose response (IUDR) curve, and b) do not necessarily imply motivation for the drug, it is unclear that median split-designated high and low drug responders represent different drug user types.

Aims

To determine if median split-designated groups of high and low drug takers represent distinct groups when subjected to a new cluster-based model.

Methods

Male Sprague Dawley rats (n = 11) self-administered cocaine doses (0.00, 0.01, 0.03, 0.1, 0.3, 0.56 and 1.00 mg/kg/infusion) to reveal the IUDR curve per individual. We derived six variables defining the structure of the IUDR curve (amplitude, mean, width, and area under the curve: AUC) and the IUDR-derived economic demand curve (consumption at zero price or Q0and the motivation for drug or α). We compared median split and clustering of all variables (cocaine dose, IUDR/demand curves) obtained.

Results

Median split of individual cocaine doses and IUDR curve-derived variables identified high versus low responders, but these groups were inconsistent with regards to group composition. Clustering of all cocaine doses revealed one cluster. Clustering of IUDR curve-derived variables revealed one cluster. Global clustering of all cocaine doses and all IUDR curve-derived variables revealed only one cluster.

Conclusions

High and low drug takers do not necessarily represent distinct drug user types.
Normalization strategies for lipidome data in cell line panels
Authors: Leegwater Hanneke , Zhang Zhengzheng , Zhang Xiaobing , Hankemeier Thomas , Harms Amy C. , Zweemer Annelien J. M. , Le Dévédec Sylvia E. , Kindt Alida
Published: July 2024

Sample collection can significantly affect measurements of relative lipid concentrations in cell line panels, hiding intrinsic biological properties of interest between cell lines. Most quality control steps in lipidomic data analysis focus on controlling technical variation. Correcting for the total amount of biological material remains an additional challenge for cell line panels. Here, we investigated how we can normalize lipidomic data acquired from multiple cell lines to correct for differences in sample biomass.

We studied how commonly used data normalization and transformation steps during analysis influenced the resulting lipid data distributions. We compared normalization by biological properties such as cell count or total protein concentration, to statistical and data-based approaches, such as median, mean, or probabilistic quotient-based normalization and used intraclass correlation to estimate how similarity between replicates changed after normalization.

Normalizing lipidomic data by cell count improved similarity between replicates, but only for a study with cell lines with similar morphological phenotypes. For cell line panels with multiple morphologies collected over a longer time, neither cell count nor protein concentration was sufficient to increase the similarity of lipid abundances between replicates of the same cell line. Data-based normalizations increased these similarities, but also created artifacts in the data caused by a bias towards the large and variable lipid class of triglycerides. This artifact was reduced by normalizing for the abundance of only structural lipids. We conclude that there is a delicate balance between improving the similarity between replicates and avoiding artifacts in lipidomic data and emphasize the importance of an appropriate normalization strategy in studying biological phenomena using lipidomics.
Multimodal MEG and microstructure-MRI investigations of the human hippocampal scene network
Authors: Lucie-Read Marie , Hodgetts Carl J. , Lawrence Andrew D. , Evans C. John , Singh Krish D. , Umla-Runge Katja , Graham Kim S.
Published: July 2024

Although several studies have demonstrated that perceptual discrimination of complex scenes relies on an extended hippocampal network, distinct from an anterotemporal network supporting the perceptual discrimination of faces, we currently have limited insight into the specific functional and structural properties of these networks. Here, combining electrophysiological (magnetoencephalography, MEG) and microstructural (multi-shell diffusion MRI, dMRI) imaging in healthy human adults (30 female/10 male), we show that both hippocampal theta power modulation and fibre restriction of the fornix (a major input/output pathway of the hippocampus) independently related to accuracy during scene, but not face, perceptual discrimination. Conversely, microstructural features of the inferior longitudinal fasciculus (a long-range occipito- anterotemporal tract) correlated with face, but not scene, perceptual discrimination accuracy. Our results provide new mechanistic insight into the neurocognitive systems underpinning complex scene and face perception, providing support for multiple-system representation-based accounts of the medial temporal lobe.

Significance Statement

In contrast to theories positing segregated cortical areas for perception and memory, the specialized representations of the hippocampus may support both the perception and memory of visual scenes. To investigate, we utilised the unique window into hippocampal electrophysiological activity offered by Magnetoencephalography (MEG). We found hippocampal theta activity modulations in the hippocampus and posteromedial cortex during scene, versus face and shape-size, perceptual oddity discrimination, the magnitude of which correlated with scene, but not face or shape- size, discrimination accuracy. Moreover, multimodal white matter imaging revealed that tissue restriction of the fornix – the major hippocampal output tract - independently predicted scene discrimination performance. Our multimodal MEG-microstructure study provides novel evidence that the hippocampus and connected structures conjointly support online scene processing.
Genetic Mapping of All Human Paralog Pairs to Characterize Synthetic Lethality and Buffering
Authors: Flister Michael J. , Verduzco Daniel , Petiwala Sakina , Carneiro-Lobo Tatiana C. , Ghekas Christos , Shi Xu , Lu Charles , Dezso Zoltan
Published: July 2024

Paralogs are abundant in the human genome and thought to be a primary source of synthetic lethality, yet the vast paralogome remains largely uncharacterized. A digenic screen of all paralogous gene pairs in the human genome revealed that synthetic lethalities were infrequent and varied in penetrance in different tumor backgrounds. We hypothesized that the variable penetrance of synthetic lethalities resulted from complex polygenic interactions with different cellular contexts. A machine learning classifier of a subset of paralog pairs tested across 49 cancer models revealed that endogenous perturbations in related pathways predicted paralog synthetic lethality. Further, predictive modeling of paralog synthetic lethality revealed that the strength of synthetic lethal interactions were largely due to the overlap and essentiality of the protein-protein interaction networks shared by the paralogs pairs. Collectively, this study tested all digenic paralog interactions and delineated the key feature classes that underlie the heterogeneity of paralog synthetic lethalities.

Highlights

Synthetic lethal paralogs have long been known, yet most paralog interactions are untested.

We report the first combinatorial screen of all 36,648 known human paralog pairs.

A meta-analysis of 461 paralog pairs in 49 cell models revealed context-dependent interactions.

The essentiality of paralog interaction networks dictate the strength of synthetic lethality.

eTOC

Synthetic lethal paralogs have long been known, yet most paralog interactions are untested. Flister et al report a screen of all 36,648 known human paralog pairs. These data combined with a meta-analysis of 461 pairs across 49 cell models revealed insights to the molecular underpinnings of context-dependent synthetic lethality.

Graphical Abstract
Interaction range of common goods shapes Black Queen dynamics beyond the cheater-cooperator narrative
Authors: Fullmer Matthew S. , van Dijk Bram , Takeuchi Nobuto
Published: July 2024

Dependencies among microorganisms often appear mutualistic in the lab, as microbes grow faster together than alone. However, according to the Black Queen (BQ) hypothesis, these dependencies are underpinned by the evolutionary benefits from loss-of-function mutations when others in the community can supply the necessary common goods. BQ dynamics often describe a cheater-cooperator scenario, where some ecotypes, the “cheaters,” produce no common goods and rely on others, the “cooperators”, for survival. We have previously proposed that in systems with multiple common goods, an alternative endpoint for BQ dynamics can emerge. This endpoint describes an ecosystem of interdependent ecotypes engaging in “mutual cheating”, i.e. where common good production isdistributed. However, even with multiple goods the common good production can becentralized, i.e. with one ecotype providing all common goods for the ecosystem. Here, we present an eco-evolutionary model that reveals that BQ dynamics can result in both distributed- or centralized common good production. The interaction range,i.e. the number of beneficiaries a producer can support, distinguishes between these two endpoints. While many ecosystems evolve to bemaximally distributedormaximally centralized, we also find intermediate ecosystems, where ecotypes that appear redundant are coexisting for long periods of time. Due to the limited interaction range, these redundant ecotypes are unable to distribute the production of common goods fully due to the presence of non-producing types. Despite non-producers thus stalling the division of labor, we observe that sudden structural shifts can occur that purge the non-producers from the ecosystem. Overall, our findings broaden the understanding of BQ dynamics, unveiling complex interactions beyond the simple cheater-cooperator narrative.
Weighted Ensemble Approach for Knowledge Graph completion improves performance
Authors: Sinha Meghamala , Tu Roger , González Carolina , Su Andrew I.
Published: July 2024

This study introduces a weighted ensemble method called “WeightedKgBlend” for link prediction in knowledge graphs which combines the predictive capabilities of two types of Knowledge Graph completion methods: knowledge graph embedding and path based reasoning. By dynamically assigning weights based on individual model performance, WeightedKgBlend surpasses standalone methods, demonstrating superior predictive accuracy when tested to discover drug-disease candidates over a large-scale biomedical knowledge graph called Mechanistic Repositioning Network. This research highlights the efficacy of an integrated approach combining multiple methods in drug discovery, showcasing improved performance and the potential for transformative insights in the realm of biomedical knowledge discovery.
Cognitive hyperplasticity drives insomnia
Authors: Huang Sheng , Piao Chengji , Zhao Zhiying , Beuschel Christine B. , Turrel Oriane , Toppe David , Sigrist Stephan J.
Published: July 2024

Sleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc)Drosophilashort sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes ofincmutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory inincmutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine toincmutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits ofincmutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.
PROTEORIZER: A holistic approach to untangle functional consequences of variants of unknown significance
Authors: Schmenger Torsten , Diwan Gaurav , Russell Robert B.
Published: July 2024

Mostin silicotools only use data closely related to the gene-of-interest or initial research question. This gene-focused research is prone to ignoring low-count and rare variants in the same or similar genes, even if available informational could be sufficient to deduce functional consequences by combining knowledge from many similar genes.

Proteorizer is a web tool that aims to bridge the gap between protein-centric knowledge and the functional context this knowledge creates. We use curated and reviewed data from UniProt to collect available residue information for the queried protein as well as orthologs. By defining functional clusters based on intramolecular distances of residues with available functional information it is possible to use these to extrapolate the effect of a VUS solely based on known functions of nearby residues, hence contextualizing the variant with pre-existing knowledge. We show that pathogenic variants are more likely to be a part of functional hotspots and present several case studies (ALPP p.Ser244Gly, CANT1 p.Ile171Phe, ARL3 p.Tyr90Cys, IL6R p.His280Pro and RAF1 p.Ser259Ala) to highlight the applicability and usefulness of this approach.

Graphical Abstract

Proteorizeris an explorative tool that takes variants from laboratory or clinical settings and contextualizes the variants based on prior information from the protein of interest and similar proteins according to where these functional positions are located in the 3D structure of the protein of interest.
PicoCam: High-resolution 3D imaging of live animals and preserved specimens
Authors: Medina Josh , Irschick Duncan , Epperly Kevin , Cuban David , Elting Rosalee , Mansfield Lucas , Lee Nora , Fernandes Ana Melisa , Garzón-Agudelo Felipe , Rico-Guevara Alejandro
Published: July 2024

1. The PicoCam system is a multi-camera photogrammetry rig used for generating high-resolution 3D models of animals in the field, or preserved specimens in laboratory or museum settings. The digital measurement of 3D models is increasingly useful for studying body shape. However, methods that capture sub-millimetric detail often do so at the cost of portability and versatility; this system aims to bridge this gap.

2. The PicoCam system employs 3D digital photogrammetry, a process that generates accurate, full-color, 3D models from sequences of photographs. By using six cameras and a rotating base, the system is able to capture multiple angles in rapid succession – a key advantage for both 3D-imaging live specimens and efficiently scanning museum specimens. Through the use of macro lenses and high-resolution camera sensors, this system can capture sub-millimetric detail without sacrificing portability.

3. In this study, we 3D imaged the bills of 19 species of hummingbirds using the PicoCam system and measured length, height, width, surface area, and volume of their bills. We examined eight species in the field and 11 from the Burke Museum in Seattle. We chose Hummingbird bills as a model system, as their fine-scale interspecific differences in 3D shape can have significant functional and behavioral implications, and could tell us more about how these traits predict habitat and resource use.

4. The prospect of a common 3D-imaging method for both museum and field use is compelling when documenting structures’ shape within and among species. The PicoCam system is also valuable for quantifying the 3D shape of fine-scale phenotypes (like hummingbird bills) that benefit from digital measurement, preservation, and improved accessibility. Lastly, the PicoCam system allows “digital 3D collection”, by which the shape of biological structures in the field can be recorded and stored in a public database without the need to collect a specimen. This opens the door to studies in which multiple 3D image captures of the same individual across different time scales permit 3D shape/color comparisons (e.g., seasonal, ontogenetic changes).
Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis
Authors: MacDonald Lucy , Elmesmari Aziza , Somma Domenico , Frew Jack , Di Mario Clara , Madhu Roopa , Paoletti Audrey , Simakou Theodoros , Hardy Olympia M. , Tolusso Barbara , Campobasso Denise , Perniola Simone , Gessi Marco , Gigante Maria Rita , Petricca Luca , Bruno Dario , Coletto Lavinia Agra , Benvenuto Roberta , Isaacs John D. , Filby Andrew , McDonald David , Sim Jasmine P. X. , Jamieson Nigel , Wei Kevin , D’Agostino Maria Antonietta , Millar Neal L. , Milling Simon , McSharry Charles , Gremese Elisa , Affleck Karen , Baker Kenneth F. , McInnes Iain B. , Otto Thomas D. , Korsunsky Ilya , Alivernini Stefano , Kurowska-Stolarska Mariola
Published: July 2024

Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to re-instate tolerance in RA. With single-cell and spatial-transcriptomics of synovial tissue biopsies, validated by micro co-culture systems, we identified condition and niche-specific myeloid DC clusters with distinct differentiation trajectories and functions. Healthy synovium contains a unique tolerogenic AXLposDC2 cluster in the superficial sublining layer. In active RA, a macrophage-rich lining-layer niche becomes populated with inflammatory DC3 clusters that specifically activate memory CCL5posTEM and CCL5posCXCL13posTPH, promoting synovitis. In the sublining lymphoid niche, CCR7posDC2 mReg specifically interact with naïve-T-cells, potentially driving the local expansion of new effector T-cells. Sustained remission sees the resolution of these niches but lacks the recovery of tolerogenic AXLposDC2, indicating latent potential for disease flare. A human RA disease-flare model showed that the activation of blood predecessor of ST-DC3 clusters precedes the onset of inflammation in joints. Therapeutic strategies targeting pathogenic ST-DC3 clusters, or reinstating tolerogenic AXLposDC2, may restore immune homeostasis in RA.

In brief

Deconstruction of human RA synovium, using single-cell spatial transcriptomics and micro-culture systems, reveals distinct neighbourhoods within the synovial architecture across health, and RA patients with active disease or sustained remission. Discrete niches are identified that contain distinct myeloid DC clusters that differ in frequency, differentiation trajectories, and effector functions.

Highlights

Human RA synovium exhibits condition and niche specific myeloid DC clusters that vary in their tissue differentiation trajectories and functions.

ST-CD14posDC3 (iDC3) support inflammatory CCL5posTEM and CCL5posTPH cell activation in the hyperplastic lining layer.

ST-CCR7posDC2 (mReg), driven by MIR155, interact with naïve-T-cells in sublining lymphoid niches.

A specific inflammatory signature of blood predecessors of ST-DC3s predict flare in RA.

Graphical abstract
The chemopreventive effects of Curcumin against oxidative stress induced by Cadmium or H2O2are mediated by Nrf2/ARE signaling and protective autophagy in myeloid cells
Authors: Russo Maria , Di Giacomo Annamaria , Fiore Federica , Spagnuolo Carmela , Carbone Virginia , Minasi Paola , Russo Gian Luigi
Published: July 2024

The evidence linking high levels of environmental pollutants to chronic degenerative diseases is alarming, with heavy metals (HM) identified as a key factor. Research suggests that certain phytochemicals in the diet can reduce HM levels and mitigate their adverse health effects.Curcumin (Cur), a natural polyphenol, is particularly effective in protecting against Cadmium (Cd) toxicity. The present study demonstrates that preincubation with low doses of Cur (1 μM) in differentiated HL-60 and K-562 human myeloid cells can significantly protect against cytotoxicity induced by Cd and or H2O2. Cur reduced the increased levels of reactive oxygen species (ROS) generated by Cd or H2O2by inducing a protective form of autophagy. Cur activated mild oxidative stress that triggers the expression of Nrf2-dependent transcripts, such as HO and NQO1. The potential chemopreventive effects of Cur against redox stress have been strengthened by the observation that free and unmetabolized Cur is detectable inside the cells after 5 minutes of treatment, and its presence parallels with increased levels of intracellular GSH. These findings suggest that supplementation with Cur in the form of nutraceuticals may represent a promising way to protect people living in highly polluted areas against the adverse effects of HM contaminants.
Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice
Authors: Wu Dan , Eeda Venkateswararao , Maria Zahra , Rawal Komal , Wang Audrey , Herlea-Pana Oana , Undi Ram Babu , Lim Hui-Ying , Wang Weidong
Published: July 2024

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional “M1-like” CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the “M1-like” CD11c+ATMs are largely overlapping with but yet non-identical to CD9+ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and “M1-like” ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.
Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import
Authors: Chang Ya-Ting , Barad Benjamin A. , Rahmani Hamidreza , Zid Brian M. , Grotjahn Danielle A.
Published: July 2024

Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to mitochondria post-translationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria inSaccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome on the surface of the mitochondria in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membrane. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.

Chang et al. present a membrane-guided approach for identifying a subset of cytoplasmic ribosomes oriented for protein import on the mitochondrial surface inSaccharomyces cerevisiaeusing cryo-electron tomography. They show that ribosomes cluster, make multiple contacts with, and induce local changes to the mitochondrial membrane ultrastructure at import sites.
Biochar Modulates Wheat Root Metabolome and Rhizosphere Microbiome in a Feedstock-dependent Manner
Authors: Yang Hanyue , Kerner Patricia , Liang Xi , Struhs Ethan , Mirkouei Amin , You Yaqi
Published: July 2024

Background

Biochar is a multifunctional soil conditioner capable of enhancing soil health and plant productivity, but the underlying mechanisms remain elusive. Here we tackled this question using wheat as a model plant and through the lens of the rhizosphere, a vital soil-plant interface continuum. We systematically examined the effects of four types of biochar (corn stover, cattle manure, pine sawdust, or wheat straw) applied at two rates (0.25% or 2.5%, w/w).

Results

Employing untargeted metabolomics and 16S rRNA gene sequencing, we revealed both common and unique modulating effects of the tested biochar treatments on wheat root metabolites and rhizosphere microbiome structure and functioning. Biochar modulated numerous metabolic pathways in wheat roots, where amino acid metabolism was the most common one, leading to cascade effects on the dynamics of a wide range of secondary metabolites, including many plant signaling molecules (e.g., flavonoid compounds, brassinosteroids) that are known to be involved in plant-microbe interactions. All biochar treatments increased rhizosphere microbial diversity, altered community composition, enhanced microbial interactions, and resulted in functional changes. Increased Burkholderiales (denitrifying bacteria) abundance and decreased Thermoplasmata (archaeal methanogens) abundance could explain biochar’s widely reported effects on nitrous oxide and methane mitigation, respectively. Biochar enhanced positive correlations among microbes and network complexity, particularly modularity, suggesting local adaptation through mutualism and/or synergism and the formation of modules of functionally interrelated taxa. A large number of diverse keystone taxa from both dominant and non-dominant phyla emerged after biochar treatments, including those known to be involved in methane, nitrogen, and sulfur cycling. Besides common alterations, treatment-specific alterations also occurred, and biochar type (i.e., feedstock choice) exerted greater influence than application rate. Wheat biochar applied at a 0.25% rate showed the strongest and distinct modulating effects, resulting in orchestrated changes in both root metabolites and rhizosphere microbiome, especially those relevant to plant-microbe interactions and likely beneficial to the host plant (e.g., upregulated biosynthesis of zeatin and down-regulated limonene degradation).

Conclusions

Our work contributes to a mechanistic understanding of how biochar modulates the soil-plant continuum and provides new insights into the potential of top-down rhizosphere microbiome engineering through biochar-based reprogramming of root-microbe interactions.
Lipoprotein(a) is Associated with Increased Low-Density Plaque Volume
Authors: Fisher Rebecca , Nurmohamed Nick , Fisher Edward A. , Aquino Melissa , Earls James P. , Min James K. , Gurevitz Chen , Malick Waqas A. , Peters M. Robert , Goonewardena Sascha N. , Rosenson Robert S.
Published: July 2024

BACKGROUND

Lipoprotein(a) [Lp(a)] is an inherited risk factor for cardiovascular disease that is accompanied by a more severe coronary artery disease (CAD) phenotype and a higher risk for events. The objective of this study is to clarify the association between Lp(a) and coronary plaque characteristics in asymptomatic patients.

METHODS

373 consecutive asymptomatic patients were evaluated for primary prevention of CAD. Artificial intelligence quantitative coronary CTA (AI-QCT) was used to investigate the relationship between Lp(a) and coronary plaque characteristics. Multivariable linear regression adjusted for CAD risk factors (age, sex, race, diabetes, smoking), statin use, and body mass index were used to analyze associations between the Lp(a) (by quintile), high sensitivity C-reactive protein (hsCRP), coronary artery calcium (CAC) score, and AI-QCT findings. AI-QCT findings were defined as low-density non-calcified plaque volume (LD-NCPV).

RESULTS

The mean age was 56.2±8.9 years, 71.6% were male, and 54.2% were taking statin therapy. Median LDL-C was 103(72,136)mg/dL, median Lp(a) was 31(11, 89)nmol/L, median Lp(a) corrected LDL-C was 101(64, 131)mg/dL. Median hsCRP levels were 0.8(0.4, 1.8)mg/L. Median CAC levels were 6.0(0.0,110.0). There was no association between Lp(a) concentrations and CAC(P=0.281). After adjustment for CAD risk factors, every quintile of Lp(a) increase was associated with a 0.4% increase in LD-NCPV(P=0.039). The inclusion of hsCRP to the models had no significant effect on LD-NCPV.

CONCLUSIONS

Higher Lp(a) concentrations in asymptomatic patients are significantly associated with increased low-density non-calcified plaque volume.

Clinical Perspective

Lp(a) is a risk marker for early-onset coronary heart disease events. Early detection of vulnerable patients is critical to mitigating this risk that may be inadequately captured by the coronary artery calcium score. Low-density non-calcified plaque quantification by coronary computerized tomography is an approach that may be more suitable to assess risk in patients with high Lp(a) levels.
Determinants of glycemic control among persons living with type 2 diabetes mellitus attending a district hospital in Ghana
Authors: ADJEI ALEXANDER , BRIGHTSON KENNEDY TETTEY COFFIE , MENSAH MICHAEL MATEY , OSEI JEMIMA , DRAH MOSES , NARH CLEMENT TETTEH , ASARE KWABENA , ANTO FRANCIS
Published: July 2024

Background Diabetes mellitus is a growing public health emergency with prevalence in sub-Sahara Africa expected to experience the highest increase by 2045. The cornerstone of diabetes management is glycemic control, a complex process with different contributing factors. This study determines the level of glycemic control and the associated individual factors among type 2 diabetes mellitus (T2DM) patients. Methods A cross-sectional descriptive study was conducted at the Shai-Osudoku District Hospital from October to December 2022. A structured questionnaire was used to collect data on socio-demographic characteristics, lifestyle modifications, co-morbidities, adherence to medication and diet regimens and duration of diabetes. Anthropometric and glycated hemoglobin (HbA1c) measurements were taken. Chi-squared and multivariate logistic regression analyses were carried out to determine factors associated with glycemic control at 95% confidence levels. Results A total of 227 patients participated in this study. The majority of the participants were females (77.97%) and the mean (+SD) age was 60.76 + 12.12 years. Good glycemic control (HbA1c < 7%) among the participants was 38.77% (n=88) and the median HbA1c was 7.5% (IQR: 6.5% to 9.4%). Significant factors associated with good glycemic control were eating healthy meals (AOR: 4.78, 95% CI: 1.65, 13.88: p=0.004), oral hypoglycemic agents alone (AOR: 15.71, 95% CI: 1.90, 129.44: p=0.010) and those with previously good glycemic control (AOR: 4.27, 95% CI: 2.16, 8.43: <0.001).   Conclusion This study showed low levels of good glycemic control among T2DM patients at the primary care level in Ghana. Healthy eating, oral hypoglycemic agents and those with previously normal HbA1c were associated with glycemic control.
Shared and unique 3D genomic features of substance use disorders across multiple cell types
Authors: Trang Khanh B. , Chesi Alessandra , Toikumo Sylvanus , Pippin James A. , Pahl Matthew C. , O’Brien Joan M. , Amundadottir Laufey T. , Brown Kevin M. , Yang Wenli , Welles Jaclyn , Santoleri Dominic , Titchenell Paul M. , Seale Patrick , Zemel Babette S. , Wagley Yadav , Hankenson Kurt D. , Kaestner Klaus H. , Anderson Stewart A. , Kayser Matthew S. , Wells Andrew D. , Kranzler Henry R. , Kember Rachel L. , Grant Struan F.A.
Published: July 2024

Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq and RNA-seq across >50 diverse human cell types to focus on genomic regions that coincide with GWAS loci. Using stratified LD regression, we determined the proportion of genome-wide SNP heritability attributable to the features assayed across our cell types by integrating recent GWAS summary statistics for the relevant traits: alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD) and cannabis use disorder (CanUD). Statistically significant enrichments (P<0.05) were observed in 14 specific cell types, with heritability reaching 9.2-fold for iPSC-derived cortical neurons and neural progenitors, confirming that they are crucial cell types for further functional exploration. Additionally, several pancreatic cell types, notably pancreatic beta cells, showed enrichment for TUD, with heritability enrichments up to 4.8-fold, suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between T2D with both TUD and CanUD (FDR<0.05) and a significant negative genetic correlation with AUD. Interestingly, after partitioning the heritability for each cell type’s cis-regulatory elements, the correlation between T2D and TUD for pancreatic beta cells was greater (r=0.2) than the global genetic correlation value. Our study provides new genomic insights into substance use disorders and implicates cell types where functional follow-up studies could reveal causal variant-gene mechanisms underpinning these disorders.