bluuebunny/crossref_metadata_2025 huggingface dataset:
Smart youth: sociodemographic factors, usage patterns, and self-reported vs. actual smartphone addiction among secondary school students
Authors: Rękas Magdalena , Burzyńska Joanna
Published: April 2024

Background

Smartphone addiction is a growing social problem especially in young mobile users. This study investigated indicators of smartphone use, smartphone addiction, and their associations with demographic and behavior-related variables in young people.

Methods

460 participants were secondary school students (Mage= 17,10, SDage= 0.92, 51.1% males, 52.4% high school students), took part in an anonymous questionnaire consisting of the following elements: the Mobile Phone Addiction Assessment Questionnaire (KBUTK), original questions regarding problematic smartphones usage, along with a subjective assessment of the use of such devices. Logistic regression model using forward stepwise method was used to characterize a typical smartphone user. Smartphone addiction was measured using KBUTK. Multiple logistic regression analysis was performed to determine factors associated with smartphone addiction.

Results

A total of 460 participants admitted to using a smartphone. Gender, age, type of school, place of living influenced the ways respondents used their smartphones. Being female (OR = 5.80;p< 0.0001), sixteen-year-old (OR = 0,41;p= 0.0456), and student of technical school (OR = 2.66;p= 0.0025) turned out to be the characteristics of a typical smartphone user. 21.7% of adolescents considered themselves addicted to smartphones, 22.2% admitted that they had problems with face-to-face relationships and girls significantly more often than boys (61.8% vs. 51.5%) neglected home or school duties as a result of using a smartphone. The overall rate of smartphone addiction was significantly higher (p< 0.0001) among girls (2.31 pts) than boys (2.03 pts), and correlated positively with the perception of being a smartphone addict (rho= 0.223;p< 0.0001). Addiction to smartphones was also significantly more common among students of technical schools, and respondents living in blocks of flats.

Conclusions

The way adolescents used smartphones differed depending on gender, age and type of school. Interventions for reducing the negative effects of smartphone use should take into account these context, as well as education both adolescents and their parents.
Antiretroviral therapy retention, adherence, and clinical outcomes among postpartum women with HIV in Nigeria
Authors: Young Clara M. , Chang Charlotte A. , Sagay Atiene S. , Imade Godwin , Ogunsola Olabanjo O. , Okonkwo Prosper , Kanki Phyllis J.
Published: April 2024

While research involving pregnant women with HIV has largely focused on the antepartum and intrapartum periods, few studies in Nigeria have examined the clinical outcomes of these women postpartum. This study aimed to evaluate antiretroviral therapy retention, adherence, and viral suppression among postpartum women in Nigeria. This retrospective clinical data analysis included women with a delivery record at the antenatal HIV clinic at Jos University Teaching Hospital between 2013 and 2017. Descriptive statistics quantified proportions retained, adherent (≥95% medication possession ratio), and virally suppressed up to 24 months postpartum. Among 1535 included women, 1497 met the triple antiretroviral therapy eligibility criteria. At 24 months, 1342 (89.6%) women remained in care, 51 (3.4%) reported transferring, and 104 (7.0%) were lost to follow-up. The proportion of patients with ≥95% medication possession ratio decreased from 79.0% to 69.1% over the 24 months. Viral suppression among those with results was 88.7% at 24 months, but <62% of those retained had viral load results at each time point. In multiple logistic regression, predictors of loss to follow-up included having a more recent HIV diagnosis, higher gravidity, fewer antenatal care visits, and a non-hospital delivery. Predictors of viral non-suppression included poorer adherence, unsuppressed/missing baseline viral load, lower baseline CD4+ T-cell count, and higher gravidity. Loss to follow-up rates were lower and antiretroviral therapy adherence rates similar among postpartum women at our study hospital compared with other sub-Saharan countries. Longer follow-up time and inclusion of multiple facilities for a nationally representative sample would be beneficial in future studies.
Differential antigenic imprinting effects between influenza H1N1 hemagglutinin and neuraminidase in a mouse model
Authors: Lv Huibin , Teo Qi Wen , Lee Chang-Chun D. , Liang Weiwen , Choi Danbi , Mao Kevin J. , Bruzzone Roberto , Wilson Ian A. , Wu Nicholas C. , Mok Chris K. P.
Published: April 2024

Understanding how immune history influences influenza immunity is essential for developing effective vaccines and therapeutic strategies. This study investigates the antigenic imprinting of influenza hemagglutinin (HA) and neuraminidase (NA) using a mouse model with sequential infection by four seasonal H1N1 strains. Our findings reveal that, among pre-2009 H1N1 strains, the extent of infection history correlates with the restriction of antibody responses to antigenically drifted HA, but not NA. This suggests the mouse model failed to recapitulate NA imprinting in humans, likely due to the difference in NA immunodominance hierarchy between humans and mice. Nevertheless, pre-existing antibodies induced by infection with pre-2009 influenza virus impeded both functional HA and NA antibody responses against a 2009 pandemic H1N1 strain. Overall, this study provides insights into antigenic imprinting for influenza virus, as well as the limitations of using mouse models for studying antigenic imprinting.

Importance

Influenza viruses continue to pose a significant threat to human health, with vaccine effectiveness being a persistent concern. One important factor is the individual immune history can influence subsequent antibody responses. While many studies have focused on how pre-existing antibodies influence the induction of anti-HA antibodies after influenza virus infections or vaccinations, the impact on anti-NA antibodies has been less extensively investigated. In this study, using a mouse model, we highlighted within the pre-2009 H1N1 strains, a greater extent of immune history negatively affected anti-HA antibodies but positively influenced anti-NA antibody responses. However, for the 2009 pandemic H1N1 strain, which underwent with antigenic shift, both anti-HA and anti-NA antibody responses have been impeded by the antibodies induced by pre-2009 H1N1 virus infection. These findings have important implications for enhancing our understanding of antigenic imprinting on anti-HA and anti-NA antibody response and for developing more effective vaccination strategies.
Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene
Authors: Garnier Olivia , Jeanneret Florian , Durand Aude , Fertin Arnold , Berndt Sarah , Carpentier Gilles , Battail Christophe , Martin Donald K. , Vilgrain Isabelle
Published: April 2024

Cancer and inflammation are associated with vascular diseases that affect endothelial cells (ECs) and alter gene expression. We aimed at understanding whether the site Y685in the cytoplasmic domain of VE-cadherin triggers epigenetic programmingin vivo. Using our knock-in mice carrying the Y685F VE-cadherin mutation, RNA sequencing from lung ECs identified 884 differentially expressed genes (DEG) involved in processes such as cell-cell adhesion, vascular development, and angiogenesis. The 30 DEGs include 22 down-regulated genes (genes encoding cell signalling enzymes, anion transport and lipid metabolism) and 8 up-regulated genes, including the endothelial-specific S1PR1. Analysis of the VEGF/VEGFR2 signaling pathway shows a significant decrease in the expression of pY1173VEGFR2 whereas VEGF remains constant, this was consistent with impaired migration, proliferation and protrusive properties of ECsin vitro. Co-immunoprecipitation experiments showed that c-Src and Y685F-VE-cadherin association which was enhanced in KI compared to WT, resulting in increased in Y685F-VE-cadherin phosphorylation at site Y731. As a consequence, its partner β-catenin translocates to the nucleus. CHIPS assay showed that FOXF1 binds to thes1pr1promoter, leading to increased expression of the S1PR1. In vivo, in the lung vasculature, this process was associated with increased vessel wall thickness and reduced fibrosis. Overall, our findings provide a novel transcriptomic profile triggered by Y685F-VE-cadherin ECs for potential insights into therapeutic targets to envisage normalisation of the tumor vasculature.
An investigation into the patterns of occupancy and detection of two endemic montane bird species, in Southern Western Ghats, India
Authors: Pop Paul
Published: April 2024

Montecincla fairbanki(Palani Laughingthrush) andSholicola albiventris(White-bellied Sholakili) are avian species found only in a few high-altitude sky islands of the Southern Western Ghats. A taxonomic revision has resulted in the need for better resolution of species biology, especially their distribution, and factors affecting their distribution. The current study was an attempt to address this, by repeated surveys at plantation sites in the northern landscape of Idukki district (Kerala), and occupancy modelling. Around 96% of the sites surveyed were occupied byM. fairbankiand ∼52% byS. albiventris. Model-averaged site-averaged occupancy probability (ψ) ofM. fairbankiis 0.8618 (0.6659-0.9229), and ofS. albiventris, it is 0.4543 (0.1358-0.9972). Model-, site-, and survey-averaged detection probability (p) ofM. fairbankiis 0.6554 (0.5171-0.7341), and ofS. albiventris, it is 0.5731 (0.4102-0.7939). This confirms the hypothesis thatS. albiventrishas lower occupancy and detection probability compared toM. fairbanki. There is likely no effect on ψ of one species by the presence of the other, but there is likely a positive effect on p of one species, by the occupancy or detection of the other. Most significant effects on ψ ofM. fairbankiwere from the exclusive presence of dirt roads, elevation, slope, and visibility, and forS. albiventris, it was fromLantana camara, elevation, and understorey height. Most significant effects on p ofM. fairbankiwere from windy weather, sky conditions, time of surveys, and survey number, whereas forS. albiventris, they were from neutral weather, and survey number. Of the interactive effects hypothesized, significant evidence was found for the increase of ψ as a function of elevation, and the reduction of ψ in the presence of the invasiveL. camara(only forS. albiventris). The insights gained from this baseline study will be useful for further hypotheses testing and conservation efforts.
The ANKS3/BICC1 protein complex is a master post-transcriptional regulator ofNPHP1ciliopathy-gene transcripts
Authors: Mahuzier Alexia , Odye Gweltas , Grampa Valentina , Bizet Albane , Viau Amandine , Ryan Rebecca , Mehraz Manon , Blisnick Thierry , Clark Euan , Henry Charline , Piedagnel Rémi , Silbermann Flora , Hayot Gaelle , De grande Line , Kahn Agathe , Plaza Jean-Marc , Krug Pauline , Knebelmann Bertrand , Muller Florian , Bastin Philippe , Sailer Andreas W. , Saint-Mezard Pierre , Jeanpierre Cécile , Hoffmann Sigrid , Benmerah Alexandre , Lelongt Brigitte , Delous Marion , Saunier Sophie
Published: April 2024

Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novelANKS3variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of theANKS3mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation ofANKS3. Finally, our results evidenced that these classically renal ciliopathy-associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH geneNPHP1and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator ofNPHP1transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.
Predicting immunotherapy response in advanced bladder cancer: a meta-analysis of six independent cohorts
Authors: Boll Lilian Marie , de Oca Sergio Vázquez Montes , Camarena Marta E. , Castelo Robert , Bellmunt Joaquim , Perera-Bel Júlia , Mar Albà M.
Published: April 2024

Advanced bladder cancer patients show very variable responses to immune checkpoint inhibitors (ICIs) and effective strategies to predict response are still lacking. Here we integrate mutation and gene expression data from 707 advanced bladder cancer patients treated with anti-PD-1/anti-PD-L1 to build highly accurate predictive models. We find that, in addition to tumor mutational burden (TMB), enrichment in the APOBEC mutational signature, and the abundance of pro-inflammatory macrophages, are major factors associated with the response. Paradoxically, patients with high immune infiltration do not show an overall better response. We show that this can be explained by the activation of immune suppressive mechanisms in a large portion of these patients. In the case of non-immune-infiltrated cancer subtypes, we uncover specific variables likely to be involved in the response. Our findings provide novel information for advancing precision medicine in patients with advanced bladder cancer treated with immunotherapy.
KIRA6 is an effective and versatile mast cell inhibitor of IgE-mediated activation
Authors: Wunderle Veronika , Wilhelm Thomas , Boukeileh Shatha , Goßen Jonas , Margreiter Michael A. , Sakurov Roman , Capellmann Sandro , Schwoerer Maike , Ahmed Nabil , Bronneberg Gina , Arock Michel , Martin Christian , Schubert Thomas , Levi-Schaffer Francesca , Rosetti Giulia , Tirosh Boaz , Huber Michael
Published: April 2024

Incidents of IgE-mediated, mast cell (MC)-driven allergic diseases are constantly rising and there is an urgent need for the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation of MCs via crosslinking of the high-affinity receptor for IgE (FcεRI) is regulated, amongst others, by the coordinated action of various cytosolic tyrosine kinases of the SRC family, e.g. LYN and FYN, which exert positive as well as negative functions. We report that KIRA6, an inhibitor developed for the endoplasmic reticulum (ER) stress sensor IRE1α, suppresses IgE-mediated pro-inflammatory MC activation by inhibiting both LYN and FYN. KIRA6 dose-dependently and effectively attenuates Ag-stimulated early signaling (e.g. substrate tyrosine phosphorylation, Ca2+mobilization, and activation of MAPK pathways) as well as effector functions such as degranulation and pro-inflammatory cytokine production/secretion in murine bone marrow-derived MCs (BMMCs). Moreover, Ag-triggered bronchoconstriction in anex vivomodel of precision-cut lung slices (PCLS), and IgE-mediated stimulation of human MCs were repressed by KIRA6. To get in-depth inside into KIRA6 interaction with three MC-relevant tyrosine kinases, LYN, FYN, and KIT, and to elicit the potential of KIRA6 structure to serve as pharmacophore for the development of respective single-, dual-, or triple-specificity inhibitors, we modeled and evaluated the binding of KIRA6 on the three kinases by applying homology modeling and molecular dynamics simulations, as well as MM GBSA calculations. We found that KIRA6 has a high propensity to bind the inactive state of LYN, FYN, and KIT with comparable affinities. In conclusion, our data suggest the use of novel inhibitors based on the KIRA6 pharmacophore as effective MC stabilizers to improve treatment of pro-inflammatory diseases with MC involvement in need of effective pharmacological interventions.
Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice
Authors: Sakurai Koki , Morita Makiko , Aomine Yoshiatsu , Matsumoto Mitsunobu , Moriyama Tetsuji , Kasahara Emiko , Sekiyama Atsuo , Otani Mayumi , Oshima Rieko , Loveland Kate L. , Yamada Masami , Yoneda Yoshihiro , Oka Masahiro , Hikida Takatoshi , Miyamoto Yoichi
Published: April 2024

Importin α4, which is encoded by theKpna4gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-κB. Here, we report thatKpna4knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-κB activity as a result ofKpna4deficiency, we observed a significant increase in expression levels of NF-κB genes and pro-inflammatory cytokines such asTNFα,Il1βorIl-6in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed thatKpna4deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin α4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity inKpna4KO cells. Taken together, importin α4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.
Familiarity modulates preference for joint feeding with conspecifics in rats
Authors: Wada Reo , Kamijo Makiko , Katsu Noriko , Hakataya Shiomi , Okanoya Kazuo , Koda Hiroki
Published: April 2024

Rats are highly social mammals that form social groups of various sizes. Interestingly, they are known to show prosocial behaviors, and are socially tolerant of other conspecifics as they feed together, but the specificity of their prosociality has not been fully understood. Here, we investigated what degree rats showed social choice, i.e., preferential joint feeding even with unfamiliar animals by performing a simple feeding site choice task. In the task, subjects were tested to choose between the feeding site where they fed with other rats (social option) or the other site where they could feed alone (solitary option). The results showed that social option choices increased particularly when the partner was a single non-cagemate rat. This result means that high social preference for other individuals occurs spontaneously, even when they are feeding with unfamiliar non-cagemates. This high degree of social tolerance would lead to the suppression of aggressive behavior as well as enhancement of affiliative relationships even in situations when the rats met with unfamiliar conspecifics for the first time.

Highlights

Rats are highly socially tolerant mammals as they feed with conspecifics together.

We explored how the presence of conspecifics affects feeding site choices in rats.

Social choices increased when the partners were non-cagemates.

Social choices decreased as the number of non-cagemates increased.

Joint feeding with a single non-cagemate is observed particularly frequently.
Data-centric AI approach for automated wildflower monitoring
Authors: Schouten Gerard , Michielsen Bas S.H.T. , Gravendeel Barbara
Published: April 2024

Both researchers and policy makers are in need of standards and tools that help understanding and assessing natural capital. Wildflowers are a major component of our natural capital; they play an essential role in ecosystems, improve soil health, supply food and medicines, and curb climate change. In this paper, we present the Eindhoven Wildflower Dataset (EWD) as well as a PyTorch object detection model that is able toidentifyandcountwildflowers. EWD, collected over two entire flowering seasons and expert annotated, contains 2002 top-view images of flowering plants captured ‘in the wild’ in five different landscape types (roadsides, urban green spaces, cropland, weed-rich grassland, marshland). It holds a total of 65571 annotations for 160 species belonging to 31 different families of flowering plants and serves as a reference dataset for automating wildflower monitoring. To ensure consistent annotations, we define specific floral count units (largely based on inflorescences) and provide extensive annotation guidelines. With a 0.82 mAP (@IoU > 0.50) score the presented baseline model, trained with a balanced subset of EWD, is to the best of our knowledge superior in its class. Our approach empowers automated quantification of wildflower richness and abundance and encourages the development of standards for AI-based wildflower monitoring. The annotated EWD dataset is publicly available on the DataverseNL research data repository, and the code to train and run the baseline model is supplied as supplementary material.
Understanding the characteristic behavior of the wild-type and mutant protein structure of FLT3 protein by computational methods
Authors: Younus Saleena , Tatli Özge , Nasimian Ahmad , Kazi Julhash U. , Rönnstrand Lars
Published: April 2024

FLT3 emerges as a commonly mutated protein with significant prognostic implications in acute myeloid leukemia (AML). Point mutations or deletions in the tyrosine kinase domain (TKD) at the activation loop and internal tandem duplications (ITD) in the juxtamembrane (JM) region (and less commonly in the TKD) are the primary mutations that occur in the FLT3 protein. Besides, AML treatment with tyrosine kinase inhibitor drugs may result in the acquisition of TKD mutations in the FLT3-ITD structure. All these mutations will induce activation of the kinase activity of FLT3 protein leading to activation of downstream signaling pathways. Therefore, finding better therapeutics against each of these mutant FLT3 proteins is crucial in the treatment of AML. This study aims to comprehend the characteristic behavior of TKD mutants (C and F in Y842), ITD mutants, and the combination of ITD with TKD mutations (C and F in Y842) in the FLT3 protein through computational approaches, including Molecular Dynamic (MD) simulation, cluster analysis, and machine learning techniques. The MD simulation studies revealed the alterations in the optimized state, flexibility, and compactness nature between FLT3-WT and mutated FLT3 proteins and identified significant changes in the point mutants, ITD, and the combined ITD and TKD mutated FLT3 protein structures. Cluster analysis also confirmed that these mutations significantly impact the overall flexibility of the protein structures, especially in the point-mutated structures of FLT3-Y842C and FLT3-ITD-Y842F. These findings emphasize the diverse protein conformations of mutated structures of the FLT3 protein, contributing to the deregulation of FLT3 protein function, and identified these mutated proteins as promising therapeutic targets in the treatment of AML.
Comprehensive Noise Reduction in Single-Cell Data with the RECODE Platform
Authors: Imoto Yusuke
Published: April 2024

Abstract

Single-cell sequencing generates vast amounts of genomic and epigenomic data from thousands of individual cells and can reveal insights into biological principles at the single-cell resolution. However, challenges such as technical noise (dropout) and batch effects hinder obtaining high-resolution structures that are essential for tasks such as the identification of rare cell types and dataset comparison across different cultures. Here, I introduceintegrative RECODE (iRECODE), a comprehensive method for noise reduction that is based on the RECODE platform, which targets the technical noise in single-cell RNA-sequencing data using high-dimensional statistics. I show iRECODE effectively mitigates both technical and batch noise with high accuracy and low computational cost. Additionally, the application of RECODE extended to other single-cell sequencing data types including single-cell Hi-C and spatial transcriptomics data and the recent enhancements in RECODE have markedly improved its accuracy and computational efficiency. Thus, the RECODE platform presents a robust solution for mitigating noise in single-cell sequencing, offering promise for advancing our understanding of biological phenomena beyond transcriptomics, encompassing epigenomic and spatial transcriptomic domains.
Luminance invariant encoding in primary visual cortex
Authors: O’Shea Ronan , Nauhaus Ian , Wei Xue-Xin , Priebe Nicholas J.
Published: April 2024

The retina maintains sensitivity over a large range of luminance intensities by switching between rod and cone photoreceptors. This luminance adaptation has been shown to alter the receptive fields and interneuronal correlations of retinal ganglion cells (RGCs). While these adaptations allow the retina to encode visual information across environmental conditions, they present a challenge to downstream processing areas for which it is important that representations are invariant to light level. We measured the effects of scotopic versus photopic luminance adaptation on thalamic and cortical activity by tracking neuronal populations across light levels. While changes in the output of the retina are evident in the lateral geniculate nucleus (LGN), the representation in primary visual cortex (V1) is largely invariant to the changes in luminance. We show that an invariant V1 code can emerge through the integration of parallel functional pathways at the geniculocortical synapse.
Dietary stress induced macrophage metabolic reprogramming, a determinant of animal growth
Authors: Mahanta Anusree , Najar Sajad Ahmad , Hariharan Nivedita , Goyal Manisha , Subramanian Ramaswamy , Giangrande Angela , Palakodeti Dasaradhi , Mukherjee Tina
Published: April 2024

Nutrient sensing and signaling play pivotal roles in animal growth. However, under dietary stress, this system falters, leading to growth defects. While immune cells are increasingly recognized as key nutrient sensors, their impact on animal growth remains poorly understood. In this study, we investigate howDrosophilalarval macrophages respond to excessive dietary sugar and identify a reconfiguration of their metabolic state. They undergo a glycolytic shift, intensify TCA activity, and elevate TAG synthesis. While typical of sugarinduced nutrient stress, these changes interestingly exert contrasting effects on animal growth: glycolysis and increased TCA activity inhibit growth, while the lipogenic shift promotes it. However, the lipogenic response is insufficient to counteract the metabolic events suppressing growth, resulting in an overall reduction in adult fly size under high sugar conditions. Stimulating a pro-lipogenic immune state facilitates growth recovery, suggesting a growth paradigm governed by immune-metabolic transitions. This study unveils the unexpected influence of macrophage metabolic reprogramming on organismal growth homeostasis duringDrosophiladevelopment, highlighting immune cell states as central determinants of growth, particularly under dietary stress.
Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels
Authors: Brisnovali Niki F. , Franco Isabelle , Abdelgawwad Amira , Tsou Hio Lam Phoebe , Cao Thong Huy , Riva Antonio , Rutter Guy A. , Akalestou Elina
Published: April 2024

Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.

Graphical Abstract

Article Highlights

The role of Sodium-glucose co-transporter type 2 (SGLT2) in immunity regulation remains elusive, despite extensive research in SGLT2 inhibitors.

We sought to discern the effects of SGLT2 inhibition or deletion on metabolic and immune profiles in high-fat-fed mice, focussing on corticosterone regulation and cytokine alterations.

SGLT2 null mice exhibit enhanced insulin sensitivity, alongside physiologically regulated corticosterone levels and significant alterations in inflammatory cytokines, and we identified changes in protein expression suggestive of antioxidant modulation.

Our findings emphasize the interplay between immune responses and metabolic regulation mediated by SGLT2 activity.
Revealing the Prevalence of Suboptimal Cells and Organs in Reference Cell Atlases: An Imperative for Enhanced Quality Control
Authors: Montserrat-Ayuso Tomàs , Esteve-Codina Anna
Published: April 2024

The advent of droplet-based single-cell RNA-sequencing (scRNA-seq) has dramatically increased data throughput, enabling the release of a diverse array of tissue cell atlases to the public. However, we will show that prominent initiatives such as the Human Cell Atlas, Tabula Muris, and Tabula Sapiens contain a significant amount of contamination products (frequently affecting the whole organ) in their data portals due to suboptimal quality filtering. Our work addresses a critical gap by advocating for more stringent quality filtering, highlighting the imperative for a shift from existing standards, which currently lean towards greater permissiveness. We will show the importance of incorporating cell intronic fraction in quality control -or MALAT1 expression otherwise- showcasing its informative nature and potential to elevate cell atlas data reliability. In summary, here, we unveil the hidden intronic landscape of every tissue and highlight the importance of more rigorous single-cell RNA-sequencing quality assessment in cell atlases to enhance their applicability in diverse downstream analyses.
Polygenic hazard score models for the prediction of Alzheimer’s free survival using the lasso for Cox’s proportional hazards model
Authors: Hahn Georg , Prokopenko Dmitry , Hecker Julian , Lutz Sharon M. , Mullin Kristina ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Tanzi Rudolph E. , DeSantis Stacia , Lange Christoph
Published: April 2024

The prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population. The aim of this work is twofold. First, we explore and advocate the idea of predicting the time dependent hazard and survival (defined as disease free time) of an individual for the onset of a disease. This provides a practitioner with a much more differentiated view of the absolute survival as a function of time. Second, to compute the time dependent risk of an individual, we use published methodology to fit a Cox’s proportional hazard model to data from a genetic SNP study of time to Alzheimer’s disease (AD) onset, using the lasso to incorporate further epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status, ten leading principal components, and selected genomic loci. We apply the lasso for Cox’s proportional hazards to a dataset of 6792 AD patients (composed of 4102 cases and 2690 controls) and 87 covariates. We demonstrate that fitting a lasso model for Cox’s proportional hazards allows one to obtain more accurate survival curves than with state-of-the-art (likelihood-based) methods. Moreover, the methodology allows one to obtain personalized survival curves for a patient, thus giving a much more differentiated view of the expected progression of a disease than the view offered by integrated risk models. The runtime to compute personalized survival curves is under a minute for the entire dataset of AD patients, thus enabling it to handle datasets with 60, 000 to 100, 000 subjects in less than one hour.
Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS
Authors: You Justin , Maksimovic Katarina , Chen Karin , Lee Jooyun , Schoeppe Anneka , Santos Jhune Rizsan , Youssef Mohieldin M. M. , Salter Michael W. , Park Jeehye
Published: April 2024

Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by theClec7agene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show thatClec7amRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3S85C/S85C) of ALS. Furthermore, a significant increase in the number of Dectin-1+microglia coincides with the onset of motor deficits, and this number increases with disease severity. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses inMatr3S85C/S85Cmice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression but could potentially serve as a valuable biomarker for ALS severity.

Subject areas

Physiology; Molecular biology; Neuroscience; Immunology

Highlights

Clec7aupregulation is confined to central nervous system regions that exhibit overt neurodegeneration in a MATR3 S85C knock-in mouse model of ALS

The appearance of Dectin-1+microglia coincides with the onset of motor deficits, and its number increases with disease progression

Knockout of Dectin-1 does not modify survival, motor deficits, neurodegeneration, or microglial responses in MATR3 S85C knock-in mice
Altered visual cortex excitatory/inhibitory ratio following transient congenital visual deprivation in humans
Authors: Pant Rashi , Pitchaimuthu Kabilan , Ossandón José , Shareef Idris , Lingareddy Sunitha , Finsterbusch Jürgen , Kekunnaya Ramesh , Röder Brigitte
Published: April 2024

Non-human animal models have indicated that the ratio of excitation to inhibition (E/I) in neural circuits is experience dependent and changes across development. Here, we assessed 3T Magnetic Resonance Spectroscopy (MRS) and electroencephalography (EEG) markers of cortical E/I ratio in ten individuals who had been treated for dense bilateral congenital cataracts, after an average of 12 years of blindness, to test for dependence of the E/I ratio in humans on early visual experience. First, participants underwent MRS scanning at rest with their eyes opened and eyes closed, to obtain visual cortex Gamma-Aminobutyric Acid (GABA+) concentration, Glutamate/Glutamine (Glx) concentration and the concentration ratio of Glx/GABA+, as measures of inhibition, excitation, and E/I ratio respectively. Subsequently, EEG was recorded to assess aperiodic activity (1-20 Hz) as a neurophysiological measure of the cortical E/I ratio, during rest with eyes open and eyes closed, and during flickering stimulation. Across conditions, congenital cataract-reversal individuals demonstrated a significantly lower visual cortex Glx/GABA+ ratio, and a higher intercept and steeper aperiodic slope at occipital electrodes, compared to age-matched sighted controls. In the congenital cataract-reversal group, a lower Glx/GABA+ ratio was associated with better visual acuity, and Glx concentration correlated positively with the aperiodic intercept in the conditions with visual input. We speculate that these findings result from an increased E/I ratio of the visual cortex as a consequence of congenital blindness, which might require commensurately increased inhibition in order to balance the additional excitation from restored visual input. The lower E/I ratio in congenital cataract-reversal individuals would thus be a consequence of homeostatic plasticity.
Flexible integration of natural stimuli by auditory cortical neurons
Authors: Ang Grace Wan Yu , Clopath Claudia , Kozlov Andriy S.
Published: April 2024

Neurons have rich input-output functions for processing and combining their inputs. Although many experiments characterize these functions by directly activating synaptic inputs on dendritesin vitro, the integration of spatiotemporal inputs representing real-world stimuli is less well studied. Using ethologically relevant stimuli, we study neuronal integration in relation to Boolean AND and OR operations thought to be important for pattern recognition. We recorded single-unit responses in the mouse auditory cortex to pairs of ultrasonic mouse vocalization (USV) syllables. We observed a range of integration responses, spanning the sublinear to supralinear regimes, with many responses resembling the MAX-like function, an instantiation of the OR operation. Integration was more MAX-like for strongly activating features, and more AND-like for spectrally distinct inputs. Importantly, single neurons could implement more than one integration function, in contrast to artificial networks which typically fix activation functions across all units and inputs. To understand the mechanism underlying the flexibility and heterogeneity in neuronal integration, we modelled how dendritic properties could influence the integration of inputs with complex spectrotemporal structure. Our results link nonlinear integration in dendrites to single-neuron computations for pattern recognition.

Significance statement

Sensory neurons compute over their inputs, combining them in ways to achieve selectivity and invariance for pattern recognition. Using real-world stimuli, we show that single cortical neurons are flexible, being capable of implementing more than one computation, unlike artificial neural-network units with fixed activation functions. We investigate this flexibility by modeling how synaptic activation patterns of real-world stimuli affect dendritic integration and the resultant neuronal computation. Our work bridges the gap between biophysical mechanisms and computation, linking neuronal input integration to pattern recognition.
ITGB6 inhibition stimulates anti-tumor responses in immunocompetent mouse models of head & neck squamous cell carcinoma and pancreatic adenocarcinoma
Authors: MacDonald William J. , Srinivasan Praveen R. , Pinho-Schwermann Maximilian , Zhang Shengliang , Tajiknia Vida , Purcell Connor , Strandberg Jillian , El-Deiry Wafik S.
Published: April 2024

ITGB6, the gene encoding the β6 subunit of integrin αvβ6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGFβ, αvβ6, and consequently, ITGB6, has considerable therapeutic implications due to the immunosuppressive effect that activated TGFβ has on the tumor microenvironment. The present study identifies ITGB6 as a potent target for inducing an immune-mediated anti-tumor response. ITGB6 is highly upregulated in various squamous cell carcinomas and pancreatic adenocarcinomas, allowing it to disrupt tumor-immune cell signaling, while avoiding the widespread side-effects of systemic TGFβ inhibition. Genetic knockout of ITGB6 in heterotopically injected head and neck squamous cell carcinoma and pancreatic adenocarcinoma cell lines showed markedly reduced tumor progression in immunocompetent mice. Additionally, co-cultures of human squamous cell carcinoma cell lines and human T-cells showed increased T-cell killing upon cancer cell ITGB6 inhibition. Colony formation experiments give further evidence that the reduction in tumor growth observed upon ITGB6 inhibitionin vivois through immunological clearance of cancer cells and not merely through intrinsic factors. Analysis of The Cancer Genome Atlas (TCGA) revealed not only the high prognostic value of ITGB6 on overall survival but also that high ITGB6 expression in patients is often associated with an inferior response to α-PD-1 and α-PD-L1 immune checkpoint blockade. The potent anti-tumor immune response observed bothin vitroandin vivoupon ITGB6 inhibition, combined with our analysis of RNA-seq data from immune checkpoint blockade-treated patients, encourages the development of ITGB6 blockade and immunotherapy combination regimes. Further pre-clinical studies will serve to facilitate the translation of our findings into therapeutic clinical trials of combination therapies for treating immunotherapy-resistant cancers.

Visual Abstract
Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype
Authors: Shvetcov Artur , Thomson Shannon , Cho Ann-Na , Wilkins Heather M. , Reed Joanne H. , Swerdlow Russell H. , Brown David A. ,   the Alzheimer’s Disease Neuroimaging Initiative, Finney Caitlin A.
Published: April 2024

INTRODUCTION

Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer’s disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.

METHODS

Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning.

RESULTS

We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells.

DISCUSSION

APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers’ vulnerability to cognitive decline and AD.
Regulation of Chromatin Modifications through Coordination of Nucleus Size and Epithelial Cell Morphology Heterogeneity
Authors: Bermudez Alexandra , Latham Zoe D. , Ma Alex J. , Bi Dapeng , Hu Jimmy K. , Lin Neil Y.C.
Published: April 2024

Cell morphology heterogeneity is pervasive in epithelial collectives, yet the underlying mechanisms driving such heterogeneity and its consequential biological ramifications remain elusive. Here, we observed a consistent correlation between the epithelial cell morphology and nucleus morphology during crowding, revealing a persistent log-normal probability distribution characterizing both cell and nucleus areas across diverse epithelial model systems. We further showed that this morphological diversity arises from asymmetric partitioning during cell division. Moreover, we provide insights into the impact of nucleus morphology on chromatin modifications. We demonstrated that constraining nucleus leads to downregulation of the euchromatic mark H3K9ac and upregulation of the heterochromatic mark H3K27me3. Furthermore, we showed that nucleus size regulates H3K27me3 levels through histone demethylase UTX. These findings highlight the significance of cell morphology heterogeneity as a driver of chromatin state diversity, shaping functional variability within epithelial tissues.
High Variability in Nicotine Analog Contents, Misleading Labeling, and Artificial Sweetener in New E-Cigarette Products Marketed as “FDA-Exempt”
Authors: Erythropel Hanno C. , Jabba Sairam V. , Silinski Peter , Anastas Paul T. , Krishnan-Sarin Suchitra , Zimmerman Julie B. , Jordt Sven E.
Published: April 2024

The recent introduction of electronic cigarette products containing a synthetic nicotine analog, 6-methyl nicotine (6MN), challenges FDA’s tobacco regulatory authority. A similar strategy is pursued by vendors of recently introduced e-cigarette liquids containing nicotinamide (NA), marketed as ‘Nixotine’ or ‘Nixamide’. Compared to nicotine, 6MN is pharmacologically more potent at nicotinic receptors, and more toxic, raising concerns about increased addictiveness and adverse effects.

Here, combinations of gas chromatography, high performance liquid chromatography and mass spectrometry were used to determine nicotine analogs, flavor and sweetener contents of e-cigarette liquids of the brands “SpreeBar” and ECBlend “Nixotine” products. All SpreeBar products, labelled as containing 5% 6-methyl nicotine, contained only 0.61-0.64% 6-methylnicotine, while “Nixotine” samples contained 7-46% less of the declared nicotinamide contents. Although “Nixotine” product labels did not list 6MN as an ingredient, small amounts of 6-methyl nicotine were detected. All ‘SpreeBar’ samples contained the artificial sweetener neotame (0.20-0.86μg/mg).

Results identified significant discrepancies between declared and measured constituents of e-cigarette products containing nicotine alternatives. The discrepancy is misleading for consumers and raises concerns about production errors. ‘SpreeBar’ products also contained neotame, a high-intensity sweetener with high heat stability, likely increasing appeal to young and first-time users. Novel e-cigarette products with misleading labels containing nicotine analogs instead of nicotine on the US market is concerning and should be urgently addressed by lawmakers and regulators.