bluuebunny/crossref_metadata_2025 huggingface dataset:
Photoelectricity generation from beet juice in a bio-electrochemical cell
Authors: Farber Yair , Rasuli David , Shlosberg Yaniv
Published: March 2024

The world is striving for the development of novel clean energy technologies that can replace the utilization of fossil fuels, and assist in the struggle against climate change. A unique approach that does not involve any carbon emission is bio-photo electrochemical cells (BPECs). This method integrates live organisms with an electrochemical system, while native redox species that exist in the organisms can generate dark and photo electrical current. Such systems were previously shown using photosynthetic micro and macro organisms in which the photocurrent mostly derives from photosynthesis. Another electron source was reported to originate from cherries which consist of pigments and enhance the production of the strong electron donor ascorbic acid under solar irradiation. In this work, we show the ability to produce electrical and photoelectrical current from beet juice. We apply cyclic voltammetry and fluorescence methods to show that among the major components that play a role in the current and photocurrent generation are NADPH and flavins.
LIPIDS MODULATE THE DYNAMICS OF GPCR:β-ARRESTIN INTERACTION
Authors: Gomes Antoniel , Di Michele Michela , Roessner Rita Ann , Damian Marjorie , Bisch Paulo M. , Sibille Nathalie , Louet Maxime , Baneres Jean-Louis , Floquet Nicolas
Published: March 2024

β-arrestins are key privileged molecular partners of G-Protein Coupled Receptors (GPCRs), triggering not only their desensitization but also intracellular signaling. Existing structures point to a high conformational plasticity of β-arrestin:GPCRs interaction, with two completely different orientations between receptor and β-arrestin. The same set of structures also indicates that the C-edge loop of β-arrestin could contribute to its anchoring to the membrane, through an interaction with specific lipids, namely PI(4,5)P2. Combining molecular dynamics simulations and fluorescence spectroscopy, we show that β-arrestin 1 interacts with membranes even in the absence of a receptor, an interaction that is enhanced by PI(4,5)P2 presumably holding the β-arrestin 1 C-edge loop into the lipid bilayer. This key interaction helps β-arrestin 1 to adopt a “receptor ready” orientation. As a consequence, PI(4,5)P2 also favors the coupling of β-arrestin 1 to the ghrelin receptor (GHSR). In addition, we show that β-arrestin can adopt the two known extreme orientations when complexed with GHSR. Of importance, PI(4,5)P2 shifts the equilibrium between the two different arrangements, favoring one of them. Simulations performed on the GHSR:β-arrestin complex suggest that release of the C-edge loop is required for these transitions to occur and point to a different distribution of PI(4,5)P2 around the complex depending on the orientation of receptor-bound arrestin. Taken together, our results highlight how PI(4,5)P2 plays a true third player role in the β-arrestin:GPCRs interaction, not only by preparing β-arrestin for its further interaction with receptors but also by modulating its orientation once the protein:protein complex is formed.
Protein disulfide isomerase disassembles stress granules and blocks cytoplasmic aggregation of TDP-43 in ALS
Authors: Liu Jia-Qi , Liu Hao , Li Yuying , Liu Xiangyi , Wang Li-Qiang , Wang Kan , Yang Zhaofei , Fu Qi , Xu Xiaojiao , Chen Jie , Zhang Yingshuang , Zhou Jun , Lei Weidong , Cui Mengchao , Liang Yi
Published: March 2024

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimer’s patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimer’s patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid–liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS patients and some Alzheimer’s patients.

Teaser

PDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS.
Unraveling the Evolutionary Trajectory of LHCI in Red-Lineage Algae: Conservation, Diversification, and Neolocalization
Authors: Kumazawa Minoru , Ifuku Kentaro
Published: March 2024

Red algae and the secondary symbiotic algae that engulfed a red alga as an endosymbiont are called red-lineage algae. They comprise key marine taxa including diatoms, Haptophyta, and Cryptophyta. Several photosystem (PS) I–light-harvesting complex I (LHCI) structures have been reported from red-lineage algae —two red algaeCyanidioschyzon merolae(Cyanidiophyceae),Porphyridium purpureum(Rhodophytina), a diatomChaetoceros gracilisand a CryptophyteChroomonas placoidea. Here, we clarified the orthologous relation of LHCIs in red-lineage algae by combining a detailed phylogenetic analysis of LHCIs and the structural information of PSI–LHCI. We found that the seven Lhcr groups in LHCI are conserved in Rhodophytina; Furthermore, during both genome reduction in Cyanidioschyzonales of red algae and endosymbiosis leading to Cryptophyta, some LHCIs were lost and replaced by existing or differentiated LHCIs. Especially in Cryptophyta, uniquely diversified Lhcrs form three sets of heterotrimers contributed to the expansion of the antenna size of PSI, supporting the modern ecological success of this taxon. We denominated “neolocalization” to these examples of flexible reorganization of LHCIs. This study provides new insights into the evolutionary process of LHCIs associated with PSI in the red-lineage algae and clarifies the need for both molecular phylogeny and structural information to elucidate the plausible evolutionary history of LHCI.
IMMUNOPHENOTYPING AND FUNCTIONAL ANALYSIS OF NK CELL SUBSETS INMycobacterium tuberculosis-INFECTED INDIVIDUALS
Authors: Silva Carolina S. , Folkesson Elin , Foroogh Fariba , Gower Maia S. , Kleberg Linn , Xi Pengjun , Sahran Dhifaf , Bruchfeld Judith , Correia-Neves Margarida , Källenius Gunilla , Sundling Christopher
Published: March 2024

Infection withMycobacterium tuberculosisremains a global health challenge, with diverse clinical outcomes ranging from latent TB (LTB) infection to active TB disease (ATB). We conducted a comprehensive analysis of NK cell subsets and function in individuals with LTB, ATB, and healthy controls to elucidate their potential association with TB pathogenesis. Peripheral blood mononuclear cells (PBMCs) were isolated from Mtb-infected individuals and analyzed by mass cytometry and flow cytometry. We identified distinct NK cell subsets and evaluated their functional responses to stimulation. Our findings revealed comparable frequencies of total and NK cell subsets across LTB, ATB, and controls. Functional assays demonstrated similar degranulation, cytokine production, and proliferation capabilities among NK cell subsets across the three groups. This study provides insights into the heterogeneity of NK cell responses in TB and highlights the need for standardized methodologies with well-characterized cohorts controlling for donor background. Further investigations are warranted to delineate the specific roles of NK cells in TB immunity and pathogenesis.
Neurodevelopmental Subtypes of Functional Brain Organization in the ABCD Study Using a Rigorous Analytic Framework
Authors: DeRosa Jacob , Friedman Naomi P. , Calhoun Vince , Banich Marie T.
Published: March 2024

The current study demonstrates that an individual’s resting-state functional connectivity (RSFC) is a dependable biomarker for identifying differential patterns of cognitive and emotional functioning during late childhood. Using baseline RSFC data from the Adolescent Brain Cognitive Development (ABCD) study, which includes children aged 9-11, we identified four distinct RSFC subtypes We introduce an integrated methodological pipeline for testing the reliability and importance of these subtypes. In the Identification phase, Leiden Community Detection defined RSFC subtypes, with their reproducibility confirmed through a split-sample technique in the Validation stage. The Evaluation phase showed that distinct cognitive and mental health profiles are associated with each subtype, with the Predictive phase indicating that subtypes better predict various cognitive and mental health characteristics than individual RSFC connections. The Replication stage employed bootstrapping and down-sampling methods to substantiate the reproducibility of these subtypes further. This work allows future explorations of developmental trajectories of these RSFC subtypes.
Rapid evolution ofKlebsiella pneumoniaebiofilmsin vitrodelineates adaptive changes selected during infection
Authors: Zaborskytė Greta , Coelho Patrícia , Wrande Marie , Sandegren Linus
Published: March 2024

Biofilm formation facilitates infection by the opportunistic pathogenKlebsiella pneumoniae, primarily through indwelling medical devices. Here, we address howK. pneumoniaecan increase its biofilm capacity by experimental evolution of surface-attached biofilms to mimic catheter-associated infections. We observed rapid convergent evolution that altered or abolished capsule, modified the fimbrial adhesin MrkD, or increased production of fimbriae and cellulose via upregulated c-di-GMP-dependent pathways. However, evolutionary trajectories and resulting phenotypes showed strain differences, illustrating the importance of genetic background on biofilm adaptation. Multiple biofilm aspects, such as early attachment, biofilm topology, surface preference, and extracellular matrix composition, were affected in a mutation-specific manner. Acute virulence was linked to the underlying genetic change rather than the overall biofilm capacity. Single mutations conferring hypermucoidy and c-di-GMP-related changes extensively overlapped with previously identified adaptive changes in UTI and wound isolates, confirming biofilm as an important selective traitin vivo.
PPIscreenML: Structure-based screening for protein-protein interactions using AlphaFold
Authors: Mischley Victoria , Maier Johannes , Chen Jesse , Karanicolas John
Published: March 2024

Protein-protein interactions underlie nearly all cellular processes. With the advent of protein structure prediction methods such as AlphaFold2 (AF2), models of specific protein pairs can be built extremely accurately in most cases. However, determining the relevance of a given protein pair remains an open question. It is presently unclear how to use best structure-based tools to infer whether a pair of candidate proteins indeed interact with one another: ideally, one might even use such information to screen amongst candidate pairings to build up protein interaction networks. Whereas methods for evaluating quality of modeled protein complexes have been co-opted for determining which pairings interact (e.g., pDockQ and iPTM), there have been no rigorously benchmarked methods for this task. Here we introduce PPIscreenML, a classification model trained to distinguish AF2 models of interacting protein pairs from AF2 models of compelling decoy pairings. We find that PPIscreenML out-performs methods such as pDockQ and iPTM for this task, and further that PPIscreenML exhibits impressive performance when identifying which ligand/receptor pairings engage one another across the structurally conserved tumor necrosis factor superfamily (TNFSF). Analysis of benchmark results using complexes not seen in PPIscreenML development strongly suggest that the model generalizes beyond training data, making it broadly applicable for identifying new protein complexes based on structural models built with AF2.
Wildlife as a sentinel for pathogen introduction in nonendemic areas: first detection ofLeishmania tropicain wildlife in Spain
Authors: Azami-Conesa Iris , Matas Méndez Pablo , Pérez-Moreno Paula , Carrión Javier , Alunda J.M. , Mateo Barrientos Marta , Gómez-Muñoz María Teresa
Published: March 2024

Leishmaniasis is a chronic global arthropod-borne zoonotic disease produced by several species ofLeishmania, with cutaneous, mucocutaneous, and visceral clinical manifestations. In Spain, onlyLeishmania infantumhas been reported so far, although other species ofLeishmania, such asL. tropicaandL. major, are present in surrounding countries.

The aim of this work is to analyze the occurrence ofLeishmaniaspp. infection in European wildcats (Felis silvestris) as sentinels, including their genotypic characterization. Necropsies of 18 road killed wildcats were conducted. Samples of ear skin and spleen were taken for DNA isolation and PCR of the highly sensitiveSSUrDNAtarget. Subsequent PCR tests were performed using more specific targets for the determination ofLeishmaniaspecies:hsp70andITS1. Positive samples were sequenced, and phylogenetic trees constructed. Seven wildcats were found positive forLeishmaniaspp.. Based on thehsp70andITS1sequences, an animal was found to be infected only withL. tropicain ear skin samples, while two cats were found to be infected withL. infantumin both the ear skin and the spleen. In one animal, a clear sequence ofL. infantumITS1 and a sequence ofL. tropica hsp70were obtained from the ear skin. Since hsp70 and ITS1 sequencing was not possible in three cats, the species ofLeishmaniainfecting them was not determined.

This is the first report of autochthonous infection withL. tropicain the Iberian Peninsula. Health care professionals, including physicians, dermatologists, and veterinarians, must be aware of this for a correct diagnosis, treatment, and management of possible co-infections.
Human circulatory system response to changes in alveolar pressure and lung volume
Authors: Semenov Yu.S. , Dyachenko A.I. , Melnikov I.S. , Zaripov R.N.
Published: March 2024

The response of hemodynamic parameters in healthy volunteers to changes in alveolar pressure and lung volume was studied by noninvasive methods during respiratory maneuvers similar to Valsalva and Müller maneuvers (in a sitting position and lying on the back horizontally). The following lung volumes and values of pressure (relative to atmospheric pressure) were considered in various combinations: total lung capacity, functional residual capacity, residual volume, -30, -15, 0, +15, +30 mmHg. Changes in hemodynamic parameters averaged over the duration of a maneuver were studied (the duration of a maneuver was 30 s). Changes in alveolar and, accordingly, intrathoracic pressure influenced hemodynamic more strongly than changes in lung volume or body position. Stroke volume decreased with increasing alveolar pressure and increased with decreasing pressure regardless of lung volume and body position; changes ranged from -35 to +15 ml. The effect of changes in alveolar pressure was more pronounced in a sitting position. Heart rate increased with increasing alveolar pressure (up to +20 bpm) but changed little with decrease in pressure. Mean arterial pressure decreased with decreasing alveolar pressure regardless of lung volume and body position; with increasing alveolar pressure, the result depended on lung volume. When performing maneuvers at total lung capacity, mean arterial pressure remained below baseline values, in other cases it increased. Changes in mean arterial pressure were within ±20 mmHg. Regardless of lung volume and body position, total peripheral resistance decreased with decreasing alveolar pressure and increased with increasing alveolar pressure; the range of changes in total peripheral resistance was -0.3 to +0.7 mmHg·s/ml.
The Area-law of Molecular Entropy: Moving beyond Harmonic Approximation
Authors: Roy Amitava , Venkatraman Vishwesh , Ali Tibra
Published: March 2024

Inspired by black hole thermodynamics, the area law that entropy is proportional to horizon area has been proposed in quantum entanglement entropy and has largely maintained its validity. This article shows that the area law is also valid for the thermodynamic entropy of molecules. We showed that the gas-phase entropy of molecules obeys the area law with our proposed correction for the different curvatures of the molecular surface. The coefficient for the ultraviolet cutoff for the molecular entropy, calculated from our curated experimental data, is tantalizingly close to the valueproposed by Hawking [Hawking, 1976]. The ability to estimate gas-phase entropy by the area law also allows us to calculate molecular entropy faster and more accurately than currently popular methods of estimating molecular entropy with harmonic oscillator approximation. The speed and accuracy of our method will open up new possibilities for the explicit inclusion of entropy in computational biology methods, such as virtual screening applications.
A mathematical model for pancreatic cancer during intraepithelial neoplasia
Authors: Briones-Andrade Joshua , Ramírez-Santiago Guillermo , Romero-Arias J. Roberto
Published: March 2024

Cancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. To understand the evolution of any type of cancer it is necessary to understand the role of the microenvironmental conditions and the impact of some molecular complexes and mechanisms on certain signalling pathways. As in most cancer quantitative models, the understanding of the early onset of cancer requires a multiscale analysis of the cellular microenvironment. In this paper we analyse a multiscale model of pancreatic adenocarcinoma by modelling the cellular microenvironment through elastic cell interactions and their intercellular communication mechanisms, such as growth factors and cytokines. We focus on the low-grade dysplasia (PanIN 1) and moderate dysplasia (PanIN 2) stages of the pancreatic adenocarcinoma. To this end we propose a gene regulatory network associated with the processes of proliferation and apoptosis of pancreatic cells and its kinetics in terms delayed differential equations to mimic cell development. Likewise, we couple the cell cycle with the spatial distribution of cells and the transport of growth factors to show that the adenocarcinoma evolution is triggered by inflammatory processes. We show that the oncogene RAS may be an important target to develop anti-inflammatory strategies that limit the emergence of more aggressive adenocarcinomas.
Neurosphere culture derived from aged hippocampal dentate gyrus
Authors: Vafaeva Olga , Namchaiw Poommaree , Murray Karl , Diaz Elva , Cheng Hwai-Jong
Published: March 2024

The neurosphere assay is the gold standard for determining proliferative and differentiation potential of neural progenitor cells (NPCs) in neurogenesis studies1–3. While severalin vitroassays have been developed to model the process of neurogenesis, they have predominantly used embryonic and early postnatal NPCs derived from the dentate gyrus (DG). A limitation of these approaches is that they do not provide insight into adult-born NPCs, which are modeled to affect hippocampal function and diseases later in life. Here, we show a novel free-floating neurosphere culture system using NPCs isolated from the DG of mature adult and aged mice.

The protocol outlines detailed steps on the isolation, propagation, and maintenance of neurospheres from adult and aged (>12 months old) mouse brain and how to differentiate cultured neurospheres into neurons and astrocytes. Culturing adult and aged NPCs provides an importantin vitromodel to (1) investigate cellular and molecular properties of this unique cell population and (2) expand the understanding of plasticity in the adult and aging brain. This protocol requires ∼2 hours to complete dissection, dissociation and culture plating, while differentiation to neuronal and astrocytic lineages takes 9 days.

By focusing on neurospheres obtained from animals at later ages this model facilitates investigation of important biological questions related to development and differentiation of hippocampal neurons generated throughout adult life.
Tuft cells act as regenerative stem cells in the human intestine
Authors: Huang Lulu , Bernink Jochem H. , Giladi Amir , Krueger Daniel , van Son Gijs J.F. , Geurts Maarten H. , Busslinger Georg , Lin Lin , Zandvliet Maurice , Peters Peter J. , López-Iglesias Carmen , Buskens Christianne J. , Bemelman Willem A. , Begthel Harry , Clevers Hans
Published: March 2024

In mice, intestinal tuft cells have been described as a long-lived, post-mitotic cell type of which two distinct subsets have been identified, named tuft-1 and tuft-21. By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase upon interleukin (IL)-4 and IL-13 exposure, as reported previously in mouse2–4. This occurs through proliferation of pre-existing tuft cells, rather than through increasedde novogeneration from stem cells. Indeed, proliferative tuft cells occurin vivoboth in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem- and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.
Whole-body connectome of a segmented annelid larva
Authors: Verasztó Csaba , Jasek Sanja , Gühmann Martin , Bezares-Calderón Luis Alberto , Williams Elizabeth A. , Shahidi Réza , Jékely Gáspár
Published: March 2024

Nervous systems coordinate effectors across the body during movements. We know little about the cellular-level structure of synaptic circuits for such body-wide control. Here we describe the whole-body synaptic connectome of a segmented larva of the marine annelidPlatynereis dumerilii. We reconstructed and annotated over 9,000 neuronal and non-neuronal cells in a whole-body serial electron microscopy dataset. Differentiated cells were classified into 202 neuronal and 92 non-neuronal cell types. We analyse modularity, multisensory integration, left-right and intersegmental connectivity and motor circuits for ciliated cells, glands, pigment cells and muscles. We identify several segment-specific cell types, demonstrating the heteromery of the annelid larval trunk. At the same time, segmentally repeated cell types across the head, the trunk segments and the pygidium suggest the serial homology of all segmental body regions. We also report descending and ascending pathways, peptidergic circuits and a multi-modal mechanosensory girdle. Our work provides the basis for understanding whole-body coordination in an entire segmented animal.
Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations
Authors: Fernández Ester Calvo , Tomassoni Lorenzo , Zhang Xu , Wang Junqiang , Obradovic Aleksandar , Laise Pasquale , Griffin Aaron T. , Vlahos Lukas , Minns Hanna E. , Morales Diana V. , Simmons Christian , Gallitto Matthew , Wei Hong-Jian , Martins Timothy J. , Becker Pamela S. , Crawford John R. , Tzaridis Theophilos , Wechsler-Reya Robert J. , Garvin James , Gartrell Robyn D. , Szalontay Luca , Zacharoulis Stergios , Wu Cheng-Chia , Zhang Zhiguo , Califano Andrea , Pavisic Jovana
Published: March 2024

Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis—whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-upin vivovalidation. While individual drugs predicted to target individual subpopulations—including avapritinib, larotrectinib, and ruxolitinib—produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.
ERNIE-RNA: An RNA Language Model with Structure-enhanced Representations
Authors: Yin Weijie , Zhang Zhaoyu , He Liang , Jiang Rui , Zhang Shuo , Liu Gan , Zhang Xuegong , Qin Tao , Xie Zhen
Published: March 2024

With large amounts of unlabeled RNA sequences data produced by high-throughput sequencing technologies, pre-trained RNA language models have been developed to estimate semantic space of RNA molecules, which facilities the understanding of grammar of RNA language. However, existing RNA language models overlook the impact of structure when modeling the RNA semantic space, resulting in incomplete feature extraction and suboptimal performance across various downstream tasks. In this study, we developed a RNA pre-trained language model named ERNIE-RNA (EnhancedRepresentations with base-pairing restriction forRNAmodeling) based on a modified BERT (Bidirectional Encoder Representations from Transformers) by incorporating base-pairing restriction with no MSA (Multiple Sequence Alignment) information. We found that the attention maps from ERNIE-RNA with no fine-tuning are able to capture RNA structure in the zero-shot experiment more precisely than conventional methods such as fine-tuned RNAfold and RNAstructure, suggesting that the ERNIE-RNA can provide comprehensive RNA structural representations. Furthermore, ERNIE-RNA achieved SOTA (state-of-the-art) performance after fine-tuning for various downstream tasks, including RNA structural and functional predictions. In summary, our ERNIE-RNA model provides general features which can be widely and effectively applied in various subsequent research tasks. Our results indicate that introducing key knowledge-based prior information in the BERT framework may be a useful strategy to enhance the performance of other language models.
Curcumin-mediated NRF2 induction limits inflammatory damage in preclinical models of cystic fibrosis
Authors: Leon-Icaza Stephen A , Fretaud Maxence , Cornélie Sarahdja , Bureau Charlotte , Yatime Laure , Floto R Andres , Renshaw Stephen A , Herrmann Jean-Louis , Langevin Christelle , Cougoule Céline , Bernut Audrey
Published: March 2024

Overactive inflammation is directly correlated with airway damage and early death in individuals with cystic fibrosis (CF), a genetic disorder caused by mutation in theCFTRgene. Reducing the impact of inflammatory damage is therefore a major concern in CF. Several studies indicate that a decrease in the nuclear factor erythroid 2-related factor-2 (NRF2) signaling in people with CF may hamper their ability to alleviate oxidative stress and inflammation, although the role of NRF2 in CF inflammatory damage has not been determined. Therefore, we examined whether the phytochemical curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF.

Herein, combiningCftr-depleted zebrafish larvae as innovative biomedical model with CF patient-derived airway organoids (AOs), we sought to understand how NRF2 dysfunction leads to abnormal inflammatory status and impaired tissue remodeling, and determine the effects of curcumin in reducing inflammation and tissue damage in CF.

We demonstrate that NFR2 is instrumental in efficiently regulating inflammatory and repair processesin vivo, thereby preventing acute neutrophilic inflammation and tissue damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin alleviates CF-associated tissue remodeling and allows tissue repair to occur. Our findings demonstrate that curcumin reduces inflammatory damage by restoring normal NRF2 activity, since disruption of Nrf2 pathway abrogated the effect of treatment in CF zebrafish.

This work highlights the protective role of NRF2 in limiting inflammation and injury, and show that therapeutic strategies to normalize NRF2 activity using curcumin might simultaneously reduce inflammation and enhance tissue repair, and thus prevent infectious and inflammatory lung damage in CF.
Stalling of Transcription by Putative G-quadruplex Sequences and CRISPR-dCas9
Authors: Hoque Mohammed Enamul , Kabir Mohammad Lutful , Shiekh Sajad , Balci Hamza , Basu Soumitra
Published: March 2024

Putative G-quadruplex forming sequences (PQS) have been identified in promoter sequences of prominent genes that are implicated among others in cancer and neurological disorders. We explored mechanistic aspects of CRISPR-dCas9-mediated gene expression regulation, which is transient and sequence specific unlike alternative approaches that lack such specificity or create permanent mutations, using the PQS in tyrosine hydroxylase (TH) andc-Mycpromoters as model systems. We performedin vitroensemble and single molecule investigations to study whether G-quadruplex (GQ) structures or dCas9 impede T7 RNA polymerase (RNAP) elongation process and whether orientation of these factors is significant. Our results demonstrate that dCas9 is more likely to block RNAP progression when the non-template strand is targeted. While the GQ inTHpromoter was effectively destabilized when the dCas9 target site partially overlapped with the PQS, thec-MycGQ remained folded and stalled RNAP elongation. We also determined that a minimum separation between the transcription start site and the dCas9 target site is required for effective stalling of RNAP by dCas9. Our study provides significant insights about the factors that impact dCas9-mediated transcription regulation when dCas9 targets the vicinity of sequences that form secondary structures and provides practical guidelines for designing guide RNA sequences.
Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates
Authors: Rekler Dina , Ofek Shai , Kagan Sarah , Friedlander Gilgi , Kalcheim Chaya
Published: March 2024

Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in-ovo inhibition of retinoic acid activity followed by single cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers indicating a failure in proper lineage segregation. Furthermore, we found that separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their critical role in establishing the roof plate-dI1 boundary.

Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. Together, we uncover and characterize a molecular mechanism responsible for segregation of dorsal neural fates during development.
D2Sim: A Computational Simulator for Nanopore Sequencing based DNA Data Storage
Authors: Sankar subhasiny , Yixin Wang , Noor-A-Rahim Md , Gunawan Erry , Guan Yong Liang , Poh Chueh Loo
Published: March 2024

DNA data storage has gained significant attention due to its high storage density and durability. However, errors during storage and reading processes compromise data integrity, prompting research into error correction strategies. Researchers have been exploring physical redundancy (data copies) and logical redundancy (added redundancy in error-correcting codes) to mitigate errors. Evaluating these designs and reconstruction methods typically involves time-consuming and costly trials. To streamline this process, We designed a computational channel simulator namely D2Sim for Nanopore sequencing-based DNA data storage. This simulator mimics real experiments, generating data with distribution and errors at the receiver. Integrated with DeepSimulator, D2Sim outputs signals closely resembling actual signals of Nanopore-based DNA storage. Comparative analysis reveals that the proposed simulator yields 16.7% to 88.7% lower sample difference deviations than signals from DeepSimulator alone. This cost-effective and time-efficient tool facilitates the assessment of physical and logical redundancy for data reconstruction in DNA data storage without the need for real-time experiments.
Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: March 2024

Acute kidney injury (AKI) is a type of renal disease occurs frequently in hospitalized patients, which may cause abnormal renal function and structure with increase in serum creatinine level with or without reduced urine output. With the incidence of AKI is increasing. However, the molecular mechanisms of AKI have not been elucidated. It is significant to further explore the molecular mechanisms of AKI. We downloaded the GSE139061 next generation sequancing (NGS) dataset from the Gene Expression Omnibus (GEO) database. Limma R bioconductor package was used to screen the differentially expressed genes (DEGs). Then, the enrichment analysis of DEGs in Gene Ontology (GO) function and REACTOME pathways was analyzed by g:Profiler. Next, the protein-protein interaction (PPI) network and modules was constructed and analysed, and the hub genes were identified. Next, the miRNA-hub gene regulatory network and TF-hub gene regulatory network were built. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. Overall, 956 DEGs were identified, including 478 up regulated and 478 down regulated genes. The enrichment functions and pathways of DEGs involve primary metabolic process, small molecule metabolic process, striated muscle contraction and metabolism. Topological analysis of the PPI network and module revealed that hub genes, including PPP1CC, RPS2, MDFI, BMI1, RPL23A, VCAM1, ALB, SNCA, DPP4 and RPL26L1, might be involved in the development of AKI. miRNA-hub gene and TF-hub gene regulatory networks revealed that miRNAs and TFs including hsa-mir-510-3p, hsa-mir-6086 and mir-146a-5p, MAX and PAX2, might be involved in the development of AKI. Various known and newtherapeutic targets were obtained via network analysis. The results of the current investigation might be beneficial for the diagnosis and treatment of AKI.
Functional associations of evolutionarily recent human genes exhibit sensitivity to the 3D genome landscape and disease
Authors: Fleck Katherine , Luria Victor , Garag Nitanta , Karger Amir , Hunter Trevor , Marten Daniel , Phu William , Nam Kee-Myoung , Sestan Nenad , O’Donnell-Luria Anne H. , Erceg Jelena
Published: March 2024

Genome organization is intricately tied to regulating genes and associated cell fate decisions. Here, we examine the positioning and functional significance of human genes, grouped by their lineage restriction level, within the 3D organization of the genome. We reveal that genes of different lineage restriction levels have distinct positioning relationships with both domains and loop anchors, and remarkably consistent relationships with boundaries across cell types. While the functional associations of each group of genes are primarily cell type-specific, associations of conserved genes maintain greater stability across 3D genomic features and disease than recently evolved genes. Furthermore, the expression of these genes across various tissues follows an evolutionary progression, such that RNA levels increase from young lineage restricted genes to ancient genes present in most species. Thus, the distinct relationships of gene evolutionary age, function, and positioning within 3D genomic features contribute to tissue-specific gene regulation in development and disease.
Do goldfish like to be informed?
Authors: Ajuwon Victor , Monteiro Tiago , Walton Mark , Kacelnik Alex
Published: March 2024

Most mammalian and avian species tested so far, including humans, prefer foretold over unsignalled future events, even if the information is costly and confers no direct benefit, a phenomenon that has been called paradoxical, or suboptimal choice. It is unclear whether this is an epiphenomenon of taxonomically widespread mechanisms of reinforcement learning, or if information-seeking is a dedicated cognitive trait, perhaps a precursor of human curiosity. We investigate whether a teleost fish that shares basic reinforcement learning mechanisms with birds and mammals also presents such preference, with the aim of dissociating food-reinforced learning from information-seeking. Goldfish chose between two alternatives, both yielding a 50% chance of reward 5s after being chosen. The ‘informative’ alternative caused immediate onset of either of two stimuli (S+ or S-) correlated with the trial’s forthcoming outcome (reward/no reward). Choosing the ‘non-informative’ option, instead triggered either of two uncorrelated stimuli (N1 or N2). Goldfish learned to discriminate between the different contingencies, but did not develop preference for the informative option. This shows that conditioning learning is not always sufficient, and the difference with birds and mammals supports the hypothesis that information-seeking, rather than simple conditioning, causes the paradoxical preference for unusable information shown by the latter.
Spec2Class: Accurate Prediction of Plant Secondary Metabolite Class using Deep Learning
Authors: Poltorak Victoria , Shachaf Nir , Aharoni Asaph , Zeevi David
Published: March 2024

Mass spectrometry (MS)-based data is commonly used in studying metabolism and natural products, but typically requires domain-specific skill and experience to analyze. Existing computational tools for non-targeted metabolite analysis (i.e., metabolomics) mostly rely on comparison to reference MS spectral libraries for metabolite identification, limiting the annotation of metabolites for which reference spectra do not exist. This is the case in plant secondary metabolites, where most spectral features remain unidentified. Here, we developedSpec2Class, a deep-learning algorithm for the identification and classification of plant secondary metabolites from liquid chromatography (LC)-MS/MS spectra. We used the in-house spectral library of 7973 plant metabolite chemical standards, alongside publicly available data, to trainSpec2Classto classify LC-MS/MS spectra to 43 common plant secondary metabolite classes. Tested on held out sets, our algorithm achieved an overall accuracy of 73%, outperforming state-of-the-art classification. We further established a prediction certainty parameter to set a threshold for low-confidence results. Applying this threshold, we reached an accuracy of 93% on an unseen dataset. We show a high robustness of our prediction to noise and to the data acquisition method.Spec2Classis publicly available and is anticipated to facilitate metabolite identification and accelerate natural product discovery.

Significance Statement

Untargeted mass spectrometry (MS) is essential for natural product discovery but is limited by product identification, which is often manual and requires domain-specific skills.Spec2Classaddresses this limitation by accurately classifying plant secondary metabolites from LC-MS/MS spectra without reliance on reference spectral libraries. Trained on a substantial dataset and using a prediction certainty threshold, it outperforms state-of-the-art algorithms with 93% accuracy. This tool demonstrates high robustness against noise and different data acquisition methods, promising to streamline metabolite identification and expedite natural product research.Spec2Classis open-source, publicly available, and easy to integrate into natural product discovery pipelines.
Dynamic role of GlyT1 as glycine sink or source: pharmacological implications for the gain control of NMDA receptors
Authors: Supplisson Stéphane
Published: March 2024

Glycine transporter 1 (GlyT1) mediates termination of inhibitory glycinergic receptors signaling in the spinal cord and brainstem, and is also diffusely present in the forebrain. Here, it regulates the ambient glycine concentration influencing the ‘glycine’-site occupancy ofN-methyl-d-aspartate (NMDARs). GlyT1 is a reversible transporter with a substantial, but not excessive, sodium-motive force for uphill transport. This study examines its potential role as a glycine source, either by reversed-uptake or by heteroexchange. I explored how glycine accumulation triggers its release, facilitating the activation of NMDARs by glutamate applied alone. Indeed, glutamate evokes no current in “naive” oocytes coexpressing GluN1/GluN2A and GlyT1, a previously characterized cellular model, but now using GlyT1 as the only potential source of coagonist for NMDAR activation. After glycine uptake, however, glutamate evokes large currents, blocked by ALX-5407 and potentiated by sarcosine, a specific inhibitor and substrate of GlyT1, respectively. These results suggest higher occupancy of the co-agonist site when GlyT1 functions as a glycine source either by reversed-uptake or by heteroexchange. A difference between these two glycine-release mechanisms occurs at hyperpolarized potentials, which induce an apparent voltage-dependent block of NMDAR currents, whereas heteroexchange preserves NMDAR activation at these potentials. Together, these results confirm GlyT1-mediated efflux as a positive regulator of NMDAR co-agonist site occupancy, and demonstrate sarcosine heteroexchange effectiveness in enhancing coagonist site occupancy. Depending on its actual mode of transport, GlyT1-inhibitors and sarcosine may have distinct effects on ambient glycine and NMDAR facilitation, and be a source of variation in reversing NMDAR hypofunction in schizophrenia.

Graphical Abstract
Large-scale composite hypothesis testing for omics analyses
Authors: De Walsche Annaïg , Gauthier Franck , Boissot Nathalie , Charcosset Alain , Mary-Huard Tristan
Published: March 2024

Composite hypothesis testing using summary statistics is a well-established approach for assessing the effect of a single marker or gene across multiple traits or omics levels. Numerous procedures have been developed for this task and have been successfully applied to identify complex patterns of association between traits, conditions, or phenotypes. However, existing methods often struggle with scalability in large datasets or fail to account for dependencies between traits or omics levels, limiting their ability to control false positives effectively. To overcome these challenges, we present the qch_copula approach, which integrates mixture models with a copula function to capture dependencies between traits or omics, and provides rigorously definedp-values for any composite hypothesis. Through a comprehensive benchmark against eight state-of-the-art methods, we demonstrate that qch_copula controls Type I error rates effectively while enhancing the detection of joint association patterns. Compared to other mixture model-based approaches, our method notably reduces memory usage during the EM algorithm, allowing the analysis of up to 20 traits and 105− 106markers. The effectiveness of qch_copula is further validated through two application cases in human and plant genetics. The method is available in the R package qch, accessible on CRAN.
Research on the matching effect between advertising appeal and product type on the purchase intention of organic food
Authors: Zhao Jiayuan , Huo Hong , Wei Sheng , Han Chunjia , Yang Mu , Gupta Brij B. , Arya Varsha
Published: March 2024

Purpose

The study employs two independent experimental studies to collect data. It focuses on the matching effect between advertising appeals and product types. The Elaboration Likelihood Model serves as the theoretical framework for understanding the cognitive processing involved in consumers' responses to these advertising appeals and product combinations.

Design/methodology/approach

This paper aims to investigate the impact of advertising appeals on consumers' intentions to purchase organic food. We explored the interaction between advertising appeals (egoistic vs altruistic) and product types (virtue vs vice) and purchase intention. The goal is to provide insights that can enhance the advertising effectiveness of organic food manufacturers and retailers.

Findings

The analysis reveals significant effects on consumers' purchase intentions based on the matching of advertising appeals with product types. Specifically, when egoistic appeals align with virtuous products, there is an improvement in consumers' purchase intentions. When altruistic appeals match vice products, a positive impact on purchase intention is observed. The results suggest that the matching of advertising appeals with product types enhances processing fluency, contributing to increased purchase intention.

Originality/value

This research contributes to the field by providing nuanced insights into the interplay between advertising appeals and product types within the context of organic food. The findings highlight the importance of considering the synergy between egoistic appeals and virtuous products, as well as altruistic appeals and vice products. This understanding can be strategically employed by organic food manufacturers and retailers to optimize their advertising strategies, thereby improving their overall effectiveness in influencing consumers' purchase intentions.