bluuebunny/crossref_metadata_2025 huggingface dataset:
The Infralimbic, but not the Prelimbic Cortex is needed for a Complex Olfactory Memory Task
Authors: Jun Dahae J. , Shannon Rebecca , Tschida Katherine , Smith David M.
Published: October 2024

The medial prefrontal cortex (mPFC) plays a key role in memory and behavioral flexibility, and a growing body of evidence suggests that the prelimbic (PL) and infralimbic (IL) subregions contribute differently to these processes. Studies of fear conditioning and goal-directed learning suggest that the PL promotes behavioral responses and memory retrieval, while the IL inhibits them. Other studies have shown that the mPFC is engaged under conditions of high interference. This raises the possibility that the PL and IL play differing roles in resolving interference. To examine this, we first used chemogenetics (DREADDs) to suppress mPFC neuronal activity and tested subjects on a conditional discrimination task known to be sensitive to muscimol inactivation. After confirming the effectiveness of the DREADD procedures, we conducted a second experiment to examine the PL and IL roles in a high interference memory task. We trained rats on two consecutive sets of conflicting odor discrimination problems, A and B, followed by test sessions involving a mid-session switch between the problem sets. Controls repeatedly performed worse on Set A, suggesting that learning Set B inhibited the rats’ ability to retrieve Set A memories (i.e. retroactive interference). PL inactivation rats performed similarly to controls. However, IL inactivation rats did not show this effect, suggesting that the IL plays a critical role in suppressing the retrieval of previously acquired memories that may interfere with retrieval of more recent memories. These results suggest that the IL plays a critical role in memory control processes needed for resolving interference.
Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR
Authors: Lusk Hannah J. , Haughan Monica A. , Bergsten Tova M. , Burdette Joanna E. , Sanchez Laura M.
Published: October 2024

Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted a mass spectrometry imaging (MSI) protocol to investigate spatial location of 3D cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid-derived metabolites in omental cocultures using LC-MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for how MSI data may produce signatures that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAA’s as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis.

SIGNIFICANCE

This study uncovers altered amino acid metabolism, specifically increased BCAA catabolism, at the interface of ovarian cancer cells and omental tissue in a coculture model of HGSOC secondary metastasis. Enhanced BCAA catabolism may promote cancer cell proliferation through mTOR signaling, presenting potential therapeutic value. These findings deepen our understanding of HGSOC pathogenesis and the metastatic tumor microenvironment, offering insights for developing new treatment strategies.
An integrative spatial multi-omic workflow for unified analysis of tumor tissue
Authors: Kriel Jurgen , Moffet Joel J.D. , Lu Tianyao , Fatunla Oluwaseun E. , Narayana Vinod K. , Valkovic Adam , Maluenda Ana , McConville Malcolm J. , Tsui Ellen , Whittle James R. , Best Sarah A. , Freytag Saskia
Published: October 2024

Combining molecular profiling with imaging techniques has advanced the field of spatial biology, offering new insights into complex biological processes. Focusing on diffuseIDH-mutated low-grade glioma, this study presents a workflow for Spatial Multi-omics Integration, SMINT, specifically combining spatial transcriptomics and spatial metabolomics. Our workflow incorporates both existing and custom-developed computational tools to enable cell segmentation and registration of spatial coordinates from both modalities to a common coordinate framework. During our investigation of cell segmentation strategies, we found that nuclei-only segmentation, while containing only 40% of segmented cell transcripts, enables accurate cell type annotation, but does not account for multinucleated cells. Our integrative workflow including cell-morphology segmentation identified distinct cellular neighborhoods at the infiltrating edge of gliomas, which were enriched in multinucleated and oligodendrocyte-lineage tumor cells, that may drive tumor invasion into the normal cortical layers of the brain.

Highlights

Alignment and integrated analysis of spatial transcriptomic and metabolomic data

Nuclei-only and cell-morphology segmentations are concordant for cell annotation

Spatially distinct regions are conserved in transcriptomic and metabolomic datasets

Multi-omic exploration of glioma leading edge identifies novel biological features
Real-cyber hybrid neural network for predicting neural circuits in mouse decision-making
Authors: Ueoka Yutaro , Maeda Hayato , Wang Shuo , Funamizu Akihiro
Published: October 2024

A major function of the brain is to make decisions by moving the physical body according to sensory inputs. Although previous studies have modeled decision-making circuits using artificial neural networks (ANNs) and compared the activity of artificial units with that of real neurons in animals, integrating ANN with actual neuronal activity has remained underexplored. Here, we developed a real-cyber hybrid neural network (HNN) that incorporates recorded neuronal activity from mice as the inputs to an ANN. This HNN both predicts whole-body movements of head-fixed mice during a task and generates unrecorded neural activity. Using spike inputs from cortical or subcortical regions, especially the parietal cortex, the HNN surpassed the ANN in predicting body movements. Notably, the HNN's artificial units exhibited activity patterns closely resembling those of real neurons in UMAP space and aligned their activity with the onset of sensory cues and behavioral choices. Furthermore, these HNN-derived units accurately decoded mouse choices, mirroring the functional properties of the recorded neurons. By compensating for unrecorded neural activity, the HNN further improved its prediction accuracy. These findings highlight the potential of HNNs in generating brain-like activity and provide new insights into the neural mechanisms that underlie animal behavior.
CELL-Diff: Unified Diffusion Modeling for Protein Sequences and Microscopy Images
Authors: Dihan Zheng , Huang Bo
Published: October 2024

Fluorescence microscopy is ubiquitously used in cell biology research to characterize the cellular role of a protein. To help elucidate the relationship between the amino acid sequence of a protein and its cellular function, we introduce CELL-Diff, a unified diffusion model facilitating bidirectional transformations between protein sequences and their corresponding microscopy images. Utilizing reference cell morphology images and a protein sequence, CELL-Diff efficiently generates corresponding protein images. Conversely, given a protein image, the model out-puts protein sequences. CELL-Diff integrates continuous and diffusion models within a unified framework and is implemented using a transformer-based network. We train CELL-Diff on the Human Protein Atlas (HPA) dataset and finetune it on the OpenCell dataset. Experimental results demonstrate that CELL-Diff outperforms existing methods in generating high-fidelity protein images, making it a practical tool for investigating subcellular protein localization and interactions.
Generation of cultured beef from bovine embryonic stem cells
Authors: Rui Xue , Li Zehan , Xu Jiehuan , Dai Jianjun , Zhang Xiaohui , Jin Xiao , Liu Yang
Published: October 2024

Bovine embryonic stem cells (bESCs) serve as an optimal source for generating muscle and fat tissues. However, systematic methodologies for creating cultured beef from bESCs have not yet been reported. Here, we successfully established a bESC line and formulated a specialized culture medium that supports cell pluripotency in both two-dimensional (2D) and three-dimensional (3D) cultures. Additionally, we have also developed serum-free and transgene-free protocols that efficiently differentiate bESCs into muscle and fat cells. These differentiated cells were validated at the transcriptional and protein levels. Furthermore, we devised a method using high moisture stretched plant-based protein scaffolds for incorporating differentiated muscle and fat cells derived from bESCs, producing an innovative plant-cell hybrid cultured beef. These advancements provide a solid foundation for future cultured beef production using pluripotent stem cells.
Speed amplitude and period affect gait variability and step followability under sinusoidal speed changing conditions
Authors: Motoyama Kiyotaka , Tashiro Takehiro , Saito Akira , Horiuchi Masahiro , Sakaki Taisuke , Abe Daijiro
Published: October 2024

Background

The time courses of the joint elevation angles of the thigh, shank, and foot in one stride during walking can be well approximated by a “plane” in a triaxial space. This intersegmental coordination (IC) of the lower limb elevation angles is called planar covariation law. Thickness of the ICplaneis associated with gait variability. This study aimed to examine how anteroposterior and lateral gait variabilities are influenced by sinusoidal speed changes with different amplitudes (±0.33 vs. ±0.67 m·s-1) and periods (30 vs. 60 s). We also questioned which limbs are responsible for the step variabilities in these conditions.

Methods

Eighteen young adults walked on a treadmill under sinusoidal speed-changing conditions with different amplitudes (±0.33 vs. ±0.67 m·s-1) and periods (30-vs. 60-s). Using 3D motion analysis system, we quantified the ICplanethickness, coefficient of variance of step width (CVSW), time delay of step length (TDSL), and step frequency (TDSF). We applied 2-way statistical parametric mapping for the time courses of each limb angle during the acceleration and deceleration phases.

Results

The ICplanethickness was greater in the ±0.67 m·s-1condition than in the ±0.33 m·s-1condition. Periods and amplitudes did not affect CVSW, TDSL, and TDSF. In the middle gait cycle, the thigh and shank were delayed in the greater amplitude condition during the acceleration phase but proceeded in the same condition during the deceleration phase.

Discussion

Sinusoidal speed amplitude influenced anteroposterior gait variability, but not lateral gait variability, regardless of period, even in healthy young adults. More distal limbs were delayed in the greater speed amplitude condition during the acceleration phase, whereas more proximal limbs proceeded in that condition during the deceleration phase, indicating that these different behaviors of the lower limb segments could be related to step variabilities.
Nonparametric serial interval estimation
Authors: Gressani Oswaldo , Hens Niel
Published: October 2024

The serial interval of an infectious disease is a key instrument to understand transmission dynamics. Estimation of the serial interval distribution from illness onset data extracted from transmission pairs is challenging due to the presence of censoring and state-of-the-art frequentist or Bayesian methods mostly rely on parametric models. We present a fully data-driven methodology to estimate the serial interval distribution based on (coarse) serial interval data. The proposal combines a nonparametric estimator of the cumulative distribution function with the bootstrap and yields point and interval estimates of any desired feature of the serial interval distribution. Algorithms underlying our approach are simple, fast and stable, and are thus easily implementable in any programming language most desired by modelers from the infectious disease community. The nonparametric routines are included in the EpiLPS package for ease of implementation. Our method complements existing parametric approaches for serial interval estimation and permits to straightforwardly analyze past, current, or future illness onset data streams.
Partial Correlation as a Tool for Mapping Functional-Structural Correspondence in Human Brain Connectivity
Authors: Santucci Francesca , Jimenez-Marin Antonio , Gabrielli Andrea , Bonifazi Paolo , Ibáñez-Berganza Miguel , Gili Tommaso , Cortes Jesus M.
Published: October 2024

Abstract

Brain structure-function coupling has been studied in health and disease by many different researchers in recent years. Most of the studies have addressed functional connectivity matrices by estimating correlation coefficients between different brain areas, despite well-known disadvantages compared to partial correlation connectivity matrices. Indeed, partial correlation represents a more sensible model for structural connectivity since, under a Gaussian approximation, it accounts only for direct dependencies between brain areas. Motivated by this and following previous results by different authors, we investigate structure-function coupling using partial correlation matrices of functional magnetic resonance imaging (fMRI) brain activity time series under different regularization (a.k.a. noise-cleaning) algorithms. We find that, across different algorithms and conditions, partial correlation provides a higher match with structural connectivity retrieved from Density Weighted Imaging data than standard correlation, and this occurs at both subject and population levels. Importantly, we also show that the precise regularization and thresholding strategy are crucial for this match to emerge. Finally, we assess neuro-genetic associations in relation to structure-function coupling, which presents promising opportunities to further advance research in the field of network neuroscience, particularly concerning brain disorders.
Identification of new targets for the diagnosis of cysts (four) and trophozoites (one) of the eye pathogenAcanthamoeba
Authors: Sundararaj Bharath Kanakapura , Goyal Manish , Samuelson John
Published: October 2024

Acanthamoebae, which are free-living amoebae, cause corneal inflammation (keratitis) and blindness, if not diagnosed and effectively treated. While trophozoites adhere to and damage the cornea,Acanthamoebacysts, the walls of which contain cellulose and have two layers connected by conical ostioles, are the diagnostic form by microscopy of the eye or of corneal scrapings. We recently used structural and experimental methods to characterize cellulose-binding domains of Luke and Leo lectins, which are abundant in the inner layer and ostioles. However, no antibodies have been made to these lectins or to a Jonah lectin and a laccase, which are abundant in the outer layer. Here we used confocal microscopy to show that rabbit antibodies to recombinant Luke, Leo, Jonah, and laccase generally support localizations of GFP-tagged proteins in walls of transfectedAcanthamoebae.Rabbit antibodies to all four wall proteins efficiently detected calcofluor white-labeled cysts of 10 of 11Acanthamoebaisolates obtained from the ATCC, including five T4 genotypes that cause most cases of keratitis. Laccase shed into the medium during encystation was detected by an enzyme-linked immunoassay. We also used structural and experimental methods to characterize the mannose-binding domain of anAcanthamoebamannose-binding protein and showed that rabbit antibodies to the mannose-binding domain efficiently detected trophozoites of all 11Acanthamoebaisolates. We conclude that four wall proteins are all excellent targets for diagnosingAcanthamoebacysts in the eye or corneal scrapings, while the mannose-binding domain is an excellent target for identifying trophozoites in cultures of corneal scrapings.

Importance

Free-living amoeba in the soil or water causeAcanthamoebakeratitis, which is diagnosed by identification of cysts by microscopy of the eye or of corneal scrapings, using calcofluor-white that unfortunately cross-reacts with fungi and plants. Alternatively,Acanthamoebainfections are diagnosed by identification of trophozoites in cultures of scrapings. Here we showed that rabbit antibodies to four abundant cyst wall proteins (Jonah, Luke, Leo, and laccase) each efficiently detect calcofluor-white-labeled cysts of 10 of 11Acanthamoebaisolates obtained from the ATCC. Further, laccase released into the medium by encystingAcanthamoebaewas detected by an enzyme-linked immunoassay. We also showed that rabbit antibodies to the mannose-binding domain of theAcanthamoebamannose-binding protein, which mediates adherence of trophozoites to keratinocytes, efficiently identifies trophozoites of all 11 ATCC isolates. In summary, four wall proteins and the ManBD appear to be excellent targets for diagnosis ofAcanthamoebacysts and trophozoites, respectively.
Plant phenotypic differentiation outweighs genetic variation in shaping the lettuce leaf microbiota
Authors: Capparotto Arianna , Chesneau Guillaume , Tondello Alessandra , Stevanato Piergiorgio , Bonato Tiziano , Squartini Andrea , Hacquard Stéphane , Giovannetti Marco
Published: October 2024

Lettuce is a widely consumed raw vegetable, making it crucial to understand and predict its leaf-associated microbial communities for the benefit of both plant and human health. While environmental factors are known to strongly influence plant leaf microbiomes, the role of plant-specific determinants in shaping microbial diversity remains unclear. In this study, we investigated the impact of three key plant factors -genetic distance, morphology and leaf micro- and macronutrient content- on the composition and diversity of lettuce leaf bacterial communities.

Using 131 fully-sequencedLactuca sativagenotypes, we analyzed their leaf-associated bacterial communities via 16S rRNA amplicon sequencing. Our findings revealed that morphological classification, as defined by breeders, exerts a greater influence on bacterial community diversity than genetic distance or variations in leaf nutrient levels. Together with shoot traits they explained 13.9% of the observed bacterial diversity. Further analysis of 10 specific leaf morphological traits showed that heart formation, head height, and venation types significantly shaped bacterial richness and evenness, mainly acting on non-hub members.

The strong association between leaf morphology and bacterial community structure suggests that phenotypic traits play a disproportionately large, yet understudied, role in leaf microbiota establishment offering new potential for manipulation by breeders.
EEG markers of vigilance, task-induced fatigue and motivation during sustained attention: Evidence for decoupled alpha- and beta-signatures
Authors: Hanzal Simon , Learmonth Gemma , Thut Gregor , Harvey Monika
Published: October 2024

Reduced vigilance can be captured in measures of attentional lapses in sustained attention tasks, but just how these lapses relate to task-induced fatigue and motivation to maintain optimal performance is unclear. We used the sustained attention to response task (SART) to induce fatigue, and manipulated motivation levels for the last block of the task in young and older participants (N = 34), while recording EEG to track electrophysiological markers of vigilance change, fatigue and motivation. Despite significant increases in subjective fatigue and mind wandering over 45 minutes, no vigilance decline was observed. However, the age groups differed markedly in their response strategies from the outset (adopting distinct speed-accuracy trade-off strategies) with faster/more erroneous responses in the younger and slower/more accurate responses in the older participants. The subjective rises in fatigue/mind wandering were coupled with an increase in pre-stimulus alpha-power, whereas the post-stimulus activity revealed two distinguishable beta signatures: a fronto-central topography as a marker of response strategy and a fronto-parietal distribution modulated by motivationper se. Our results thus show three distinct neural patterns underpinning the effects of fatigue, response strategy and motivation and suggest a (motivational) cognitive control mechanism behind resetting of performance decrement, independent of persistent fatigue.
PD-L1+ Neutrophils mediate Susceptibility during Systemic Inflammatory Response in Non-Alcoholic Fatty Liver Disease
Authors: Barros Cleyson da Cruz Oliveira , Kanashiro Alexandre , da Silva Gabriel Victor Lucena , Cebinelli Guilherme Cesar Martelossi , Leiria Luiz Osório , Cunha Thiago Mattar , Alves Filho José Carlos , Cunha Fernando Queiroz
Published: October 2024

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition affecting individuals worldwide. Patients with NAFLD are more susceptible to systemic inflammation, such as sepsis, which accelerates liver damage. However, the immunological mechanisms that trigger the hyper-inflammatory responses in individuals with NAFLD remain unknown. In the present study, we reported that short-term HFCD (Choline Deficient High Fat Diet)-fed mice, which did not show significative signs of hepatic damage and inflammation in the first two weeks, are more susceptible to mortality after lipopolysaccharide (LPS) challenge. Mechanistically, endotoxemic mice show an excessive accumulation of NK-producing IFN-γ cells in liver tissue triggering the recruitment and polarization of a distinct neutrophil subset, characterized by high PD-L1 expression and massive TNFα production. Remarkably, genetic inhibition of IFN-γ or pharmacological blockade of PD-L1 effectively modulated the excessive recruitment of these neutrophils to the liver and TNFα release, thereby preventing hepatic damage and reducing the severity of host mortality. Thus, these results support the design of novel effective strategies to control hyperinflammatory responses in patients with HFCDs and consequently prevent hepatic damage and mortality..
Sustainability in the laboratory: evaluating the reuseability of microtiter plates for PCR and fragment detection
Authors: Berthelsen Ane Liv , Paijmans Anneke J. , Forcada Jaume , Hoffman Joseph Ivan
Published: October 2024

1.

Single-use plastics (SUPs) are indispensable in laboratory research, but their disposal contributes substantially to environmental pollution. Consequently, reusing common SUP items such as microtiter plates represents a promising strategy for improving laboratory sustainability. However, the key challenge lies in determining whether SUP reuse can be implemented without sacrificing data quality. To investigate this, we conducted a simple experiment to assess the impact of reusing microtiter plates on microsatellite genotyping accuracy. Plates previously used for PCR and fragment detection were cleaned opting for an environmentally friendly approach using regular soap and then reused. Our results indicate that, while reusing PCR plates significantly increases genotyping error rates due to residual DNA contamination, detection plates can be reused without compromising data quality. Our approach offers laboratories a practical and sustainable option for reducing SUP waste and costs while maintaining research integrity.
Elucidating the neuropathological and molecular heterogeneity of amyloid-beta and tau in Alzheimer's disease through machine learning and transcriptomic integration
Authors: Zhao Kanhao , Xie Hua , Jacobs Tovia , Gaggi Naomi L , Fortea Juan , Carlisle Nancy B , Fonzo Gregory A , Pohl Kilian M , Osorio Ricardo S , Zhang Yu
Published: October 2024

Discerning functional brain network variations related to neuropathological aggregates in Alzheimer's disease (AD), including amyloid-beta (Abeta) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimer's continuum cases (Abeta positive (A+), n = 129) and normal elderly (Abeta negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual Abeta and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the Aβ-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimer's continuum pathological biomarkers.
Ductal pancreatic cancer interception by FGFR2 abrogation
Authors: Tonelli Claudia , Deschênes Astrid , Gaeth Victoria , Jensen Amanda , Vithlani Nandan , Yao Melissa A. , Zhao Zhen , Park Youngkyu , Tuveson David A.
Published: October 2024

Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDA) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. The pathways that cooperate with mutant KRAS to induce tumorigenesis are less-defined. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively up-regulated in mutant KRAS-driven metaplasia, pre-neoplasia and Classical PDA. Using genetic mouse models, we showed that FGFR2 supported mutant KRAS-driven transformation of acinar cells by promoting proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, we discovered that FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-neoplastic lesion formation.

Together, our data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.

STATEMENT OF SIGNIFICANCE

Mutant KRAS-expressing pancreatic intraepithelial neoplasias (PanINs), the precursor lesions of PDA, are prevalent in the average healthy adult but rarely advance to invasive carcinoma. Here, we discovered that FGFR2 promoted PDA progression by amplifying mutant KRAS signaling and that inactivation of FGFR2 intercepted disease progression.
Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors
Authors: Zhang Xiujuan , Hao Siyuan , Feng Zehua , Ning Kang , Kuz Cagla Aksu , McFarlin Shane , Richart Donovan , Cheng Fang , Zhang-Chen Ander , McFarlane Richenda , Yan Ziying , Qiu Jianming
Published: October 2024

We conducted a genome-wide CRISPR/Cas9 screen in suspension 293-F cells transduced with rAAV5. The highly selected genes revealed after two rounds of screens included the previously reportedKIAA039L,TM9SF2, andRNF121, along with a cluster of genes involved in glycan biogenesis, Golgi apparatus localization and endoplasmic reticulum penetration. In this report, we focused on solute carrier family 35 member A1 (SLC35A1), a Golgi apparatus-localized cytidine 5’-monophosphate-sialic acid (CMP-SIA) transporter. We confirmed thatSLC35A1knockout (KO) significantly decreased rAAV5 transduction to a level lower than that observed inKIAA0319LorTM9SF2KO cells. AlthoughSLC35A1KO drastically reduced the expression of α2,6-linked SIA on the cell surface, the expression of α2,3-linked SIA, as well as the cell binding and internalization of rAAV5, were only moderately affected. Moreover,SLC35A1KO significantly diminished the transduction of AAV multi-serotypes, including rAAV2 and rAAV3 which do not utilize SIAs for primary attachment. Notably, the SLC35A1 KO markedly increased transduction of rAAV9 and rAAV11, which primarily attach to cells via binding to galactose. Further analyses revealed thatSLC35A1KO significantly decreased vector nuclear import. More importantly, although the C-terminal cytoplasmic tail deletion (ΔC Tail) mutant of SLC35A1 did not drastically decrease SIA expression, it significantly decreased rAAV transduction, as well as vector nuclear import, suggesting the C-tail is critical in these processes. Furthermore, the T128A mutant significantly decreased SIA expression, but still supported rAAV transduction and nuclear import. These findings highlight the involvement of the CMP-SIA transporter in the intracellular trafficking of rAAV vectors post-internalization.

IMPORTANCE

rAAV is an essential tool for gene delivery in the treatment of genetic disorders, yet the mechanisms of rAAV transduction remain partially understood. GPR108 is vital for the transduction of most rAAV vectors, but not for rAAV5. We aimed to identify host factors that impact AAV5 transduction akin to GPR108. Using a genome-wide CRISPR/Cas9 screen in 293-F cells, we identified SLC35A1, a Golgi apparatus-localized CMP-sialic acid transporter that transports CMP-sialic acid from cytoplasm into the Golgi apparatus for sialylation, is essential to rAAV transduction. Further studies across various AAV serotypes showed SLC35A1 significantly affects vector nuclear import post-internalization. These results underscore the crucial role of SLC35A1 in intracellular trafficking beyond the initial cell attachment of rAAV.
Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease
Authors: Du Muzi , Akerman Suleyman C. , Fare Charlotte M. , Ruan Linhao , Vidensky Svetlana , Mamedova Lyudmila , Lee Joshua , Rothstein Jeffrey D.
Published: October 2024

TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studiedin vivousing animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models ofC9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer’s disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer’s disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data fromin vivomouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.
Modeling the potential impacts of outpatient antiviral treatment in reducing influenza-associated hospitalizations in the United States
Authors: Morris Sinead E. , Mathis Sarabeth M. , Reeves Emily , Chung Jessie R. , Borchering Rebecca K. , Lewis Nathaniel M. , Masalovich Svetlana , Garg Shikha , Uyeki Timothy M. , Iuliano A. Danielle , Tenforde Mark W. , Reed Carrie , Biggerstaff Matthew
Published: October 2024

Background

Seasonal influenza causes an estimated 100,000–710,000 hospitalizations annually in the United States (U.S.). Treatment with antiviral medications, such as oseltamivir, can reduce risks of hospitalization among people with influenza-associated illness. The U.S. Centers for Disease Control and Prevention recommends initiating antiviral treatment as soon as possible for outpatients with suspected or confirmed influenza who have severe or progressive illness or are at higher risk of influenza complications.

Methods

We developed a probabilistic model to estimate the impact of antiviral treatment in reducing hospitalizations among U.S. outpatients with influenza. Parameters were informed by seasonal influenza surveillance platforms and stratified by age group and whether individuals had a medical condition associated with higher risk of influenza complications. We modeled different scenarios for influenza antiviral effectiveness and outpatient testing and prescribing practices, then compared our results to a baseline scenario in which antivirals were not used.

Results

Across the modeled scenarios, antiviral treatment resulted in 1,215–14,184 fewer influenza-associated hospitalizations on average compared to the baseline scenario (a 0.2%–2.7% reduction). The greatest effects occurred among adults ≥65 years and individuals with conditions associated with higher risk of influenza complications. Modeling 50% improvements in access to care, testing, prescribing, and treatment resulted in greater potential impacts, with over 71,000 (13.3%) influenza-associated hospitalizations averted on average compared to baseline.

Conclusions

Our results support recommendations to prioritize outpatient antiviral treatment among older adults and others at higher risk of influenza complications. Improving access to prompt testing and treatment among outpatients with suspected influenza could reduce hospitalizations substantially.

We probabilistically modeled influenza antiviral treatment among outpatients with influenza virus infection in the United States. Antiviral treatment reduced influenza-associated hospitalizations, with the greatest impacts among adults ≥65 years and persons with conditions associated with higher risk of influenza complications.
Mammary Epithelial Migration is EMT-Independent
Authors: Chen Jing , ma Rongze , Deng Zhixuan , Lu Yunzhe , Zhou Jiecan , Xia Kun , Klein Ophir D. , Lu Pengfei
Published: October 2024

Epithelial tissues are traditionally considered immobile, requiring epithelial-to-mesenchymal transition (EMT) for individual or collective cell migration as mesenchymal cells. However, recent studies indicate that the mammary epithelium migrates via mechanisms distinct from mesenchymal collectives. Here, we demonstrate that mammary epithelium does not undergo EMT before migration, as evidenced by cellular and molecular characteristics, including EMT marker expression at the mRNA, protein, localization, and transcriptomic levels. Contrary to established models, cell-cell adhesion is not diminished but is required for epithelial migration. Furthermore,Snail1does not repress cell-cell adhesion but instead plays a pivotal role in directing epithelial migration by regulating processes such as the directional movement of individual cells viaCdc42ep5. Our findings reveal the existence of both stationary and migratory states within the epithelium, providing new insights into how epithelial tissues transition between these states, with broad implications for organogenesis and cancer biology.
Knowledge Graphs and Explainable AI for Drug Repurposing on Rare Diseases
Authors: Perdomo-Quinteiro P. , Wolstencroft K. , Roos M. , Queralt-Rosinach N.
Published: October 2024

Artificial Intelligence (AI)-based drug repurposing is an emerging strategy to identify drug candidates to treat rare diseases. However, cutting-edge algorithms based on Deep Learning (DL) typically don’t provide a human understandable explanation supporting their predictions. This is a problem because it hampers the biologists’ ability to decide which predictions are the most plausible drug candidates to test in costly lab experiments. In this study, we proposerd-explainera novel AI drug repurposing method for rare diseases which obtains possible drug candidates together with human understandable explanations. The method is based on Graph Neural Network (GNN) technology and explanations were generated as semantic graphs using state-of-the-art eXplainable AI (XAI). The model learns features from current background knowledge on the target rare disease structured as a Knowledge Graph (KG), which integrates curated facts and their evidence on different biomedical entities such as symptoms, drugs, genes and ortholog genes. Our experiments demonstrate that our method has excellent performance that is superior to state-of-the-art models. We investigated the application of XAI on drug repurposing for rare diseases and we prove our method is capable of discovering plausible drug candidates based on testable explanations. The data and code are publicly available athttps://github.com/PPerdomoQ/rare-disease-explainer.

Highlights

We demonstrated the use of graph-based explainable AI for drug repurposing on rare diseases to accelerate sound discovery of new therapies for this underrepresented group.

We developedrd-explainerfor rare disease specific drug research for faster translation. It predicts drugs to treat symptoms/phenotypes, it is highly performant and novel candidates are plausible according to evidence in the scientific literature and clinical trials. Key is that it learns a GNN model that is trained on a knowledge graph built specifically for a rare disease. We providerd-explainercode freely available for the community.

rd-explaineris researcher-centric interpretable ML for hypothesis generation and lab-in-the-loop drug research. Explanations of predictions are semantic graphs in line with human reasoning.

We detected an effect of knowledge graph topology on explainability. This highlights the importance of knowledge representation for the drug repurposing task.
Hydroxyurea induces ER stress and cytoplasmic protein aggregation
Authors: Sánchez-Molina Ana , Bernal Manuel , Posligua-García Joel D. , Pérez-Pulido Antonio J. , de Cubas Laura , Hidalgo Elena , Salas-Pino Silvia , Daga Rafael R.
Published: October 2024

The endoplasmic reticulum (ER) lumen provides the proper redox environment for disulfide bond formation, which is required for the appropriate folding of proteins that enter the secretory pathway and constitute membranes. Defective protein folding in the ER activates proteostatic mechanisms that are now beginning to be elucidated. Here, we show that hydroxyurea (HU) causes ER stress and triggers a transient perinuclear ER expansion, which leads to the clustering of nuclear pore complexes. This striking phenotype is mimicked by diamide (DIA), a specific thiol stress inductor, and prevented or rapidly reverted by dithiothreitol, a dithiol-reducing agent, suggesting that ER expansion is caused by disulfide stress. ER expansion induced by HU or DIA depends on glutathione (GSH), is Ire1-independent, and is associated with a unique transcriptome program that differs from the canonical unfolding protein response (UPR). The ER luminal expansion accumulates Hsp70 Bip1 chaperone, and it evolves parallel with the appearance of cytoplasmic protein aggregates containing heat stress proteins (HSPs), indicating that both HU and DIA are impinging on protein folding. Thus, our data reveal that HU induces disulfide stress that impinges on protein folding in the cytoplasm and ER.
Optical manipulation of spin states in ultracold magnetic atoms via an inner-shell hz transition
Authors: Claude F. , Lafforgue L. , Houwman J. J. A. , Mark M. J. , Ferlaino F.
Published: October 2024

Lanthanides, like erbium and dysprosium, have emerged as powerful platforms for quantum-gas research due to their diverse properties, including a significant large spin manifold in their absolute ground state. However, effectively exploiting the spin richness necessitates precise manipulation of spin populations, a challenge yet to be fully addressed in this class of atomic species. In this work, we present an all-optical method for deterministically controlling the spin composition of a dipolar bosonic erbium gas, based on a clocklike transition in the telecom window at 1299nm. The atoms can be prepared in just a few tens of microseconds in any spin-state composition using a sequence of Rabi-pulse pairs, selectively coupling Zeeman sublevels of the ground state with those of the long-lived clocklike state. Finally, we demonstrate that this transition can also be used to create spin-selective light shifts, thus fully suppressing spin-exchange collisions. These experimental results unlock exciting possibilities for implementing advanced spin models in isolated, clean, and fully controllable lattice systems.

Published by the American Physical Society
2024
Determinants of consumers’ attitude towards mobile wallet adoption in Somalia
Authors: Mukhtar Yonis Ali , Barre Galad Mohamed
Published: October 2024

Purpose

This study aims to empirically investigate the factors that influence consumers' attitudes and intentions to use mobile wallets in the context of Somalia. Additionally, the study examines the role of attitude as a mediator between independent variables and the dependent variable.

Design/methodology/approach

A multidisciplinary model is proposed, building on the Technology Acceptance Model (TAM), the Unified Theory of Acceptance and Use of Technology (UTAUT) and other relevant research on factors influencing technology adoption. Data were collected using a questionnaire, and convenience sampling was employed to select the respondents. A total of 321 respondents participated in the survey. Fifteen hypotheses were formulated, and PLS-SEM and SPSS software were used to estimate and test the hypothesized model.

Findings

The results show that factors including attitude, lifestyle condition (LC), perceived ease of use (PEOU) and perceived usefulness (PU) have a direct effect on the intention to use mobile wallets. However, facilitating conditions (FC), quality of internet connection (QIC), security (SEC) and trust do not have a direct effect on mobile wallet adoption. On the other hand, attitude mediates the relationship between facilitating conditions, lifestyle compatibility, perceived ease of use, perceived usefulness, quality of internet connection, security and mobile wallet adoption. Consumer attitude does not mediate the relationship between trust and mobile wallet adoption.

Research limitations/implications

This empirical study was conducted only in Mogadishu, thus limiting its geographic scope. Future research on mobile wallets should consider more cities in Somalia. The data were collected at a specific point in time. Given the rapidly changing rate of mobile wallet usage, a longitudinal study might be warranted. Additionally, other variables such as relative advantage, perceived benefits, risk and additional factors could be considered.

Practical implications

As lifestyle conditions, perceived ease of use and perceived usefulness emerged as important constructs for mobile wallet acceptance, there is a need to develop the best ease of use, the most suitable conditions and the highest perceived usefulness. The findings have managerial implications that can help banks providing mobile wallet services to increase the usage and adoption of their services.

Originality/value

Mobile wallets have introduced new digital payment options for consumers while also providing businesses and marketers with enhanced opportunities to promote their products and services online. However, there is limited research on the adoption of mobile wallets in Somalia. This study may be the first in Somalia to investigate mobile wallet adoption with a larger sample size compared to previous studies. It also proposes and validates additional constructs not included in the original model.
Empowering farmer community with technology modernisation to improve rice farming performance through demonstration farms in East Java, Indonesia
Authors: Mariyono Joko , Kuntariningsih Apri
Published: October 2024

Purpose

Rice is a strategic commodity and staple food; thus, rice productivity should grow faster than the population. A public agricultural agency launched technology modernisation to improve rice farm performance. This study aims to assess the impact of technology modernisation on rice farming performance and evaluate farmer acceptance of such technology.

Design/methodology/approach

This study was conducted in 2023-2024, based on selected demonstration farms (demfarm) carried out during 2021-2022 in East Java, Indonesia, one of the rice bowls. Microeconomic theory of production and the double-differences approach were used as fundamental analyses. Farmers were purposively selected to participate in the demfarm. For comparison, farmers with existing technology adjacent to the demfarm were chosen accordingly. Rice production is considered an economic performance indicator, and factors related to socio-demographic and technical aspects were conceptualised using innovation and diffusion theory.

Findings

The results of demfarm were apparent. Technology modernisation improved rice farming’s economic performance. Farmer acceptance of such technology was relatively high at the first stage. There was no conflict between technology and local culture and norms. The technological package will likely be disseminated to farmers after adequate socialisation.

Research limitations/implications

This study engaged farmer innovators and early adopters in the demonstration farm. This needs more actions from farmers who are not categorised as innovators and early adopters, which dominate the farmer population.

Practical implications

Extension officials need field guidance to ensure continual technology adoption because of technology complexity.

Originality/value

The originality of the study is based on a field experiment and direct observation throughout a crop cycle, and the analysis is established using a solid theory and analytical framework.