bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient and Safe Trans-complementation System for MPXV Mimicking Authentic Viral Infection
Authors: Liu Jianying , Zhu Longchao , Mei Lingling , Liu Yuanyuan , Qu Yuanyuan , Yuan Yulin , Zhang Fenfen , Cao Yingyi , Zhu Yibin , Tai Wanbo , Ma Jun , Zheng Min , Shi Xiaolu , Liu Yang , Cheng Gong
Published: December 2023

Since the Mpox virus (MPXV) outbreak in 2022, there have been 97,745 cases and 203 fatalities. This outbreak features increased transmission efficiency and a higher infection rate in the MSM population, with the underlying causes remaining unknown. The requirement of BSL-3 laboratories poses a barrier to MPXV research and antiviral development. Here, we report an efficient and safe trans-complementary system that produces a single-round infectious MPXV, preserving the virus’s authentic architecture and enabling it to complete its life cycle in complementing cells. This deficient MPXV genome, lacking two essential genes crucial for late gene transcription and viral assembly, is restricted to a single-round infection in non-complementing cell lines. Notably, SCID mice inoculated with this deficient MPXV exhibited no detectable disease or viral load. This deficient MPXV platform has demonstrated its capacity to study innate immunity and cell death during infection in complementing cells. It can also be used for antibody neutralization assays and anti-MPXV drug evaluation. This trans-complementation platform, safe for use in low-biosafety laboratories, offers a valuable resource for MPXV research and countermeasure development.
Anti-dengue viral activity of Glycyrrhiza glabra roots in Vero cells
Authors: Jayasekera Kalani Gayathri , Suresh Sugandhika , Goonasekera Charitha , Soyza Preethi , Perera Namal , Jayawardene Amitha , gunasekera kamani
Published: December 2023

Dengue is a global public health problem but no antiviral agent exists for dengue. Plants have been the source of many pharmaceutical agents. Therefore, we explored the antiviral potential of the aqueous extracts of Glycyrrhiza glabra (GG) roots on dengue viruses. Cell cytotoxicity assay with 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide solution was used for estimating the maximum nontoxic dose (MNTD) and 50% cytotoxic concentration (CC50). Plaque reduction antiviral assay on Vero cells infected with dengue virus serotypes 1,2,3 and 4 were treated with dilutions of the MNTD of GG extract to calculate the half maximal inhibitory concentration (IC50). Selectivity index (SI) was calculated as CC50/IC50 ratio. Following bioactivity guided fractionation, MNTD, CC50, IC50 and SI values for fractions E and F were similarly obtained. Inhibition of NS1 antigen levels produced by dengue serotype-1 infected monocytes was studied in the presence and absence of GG extract after 48 hours. GG MNTD and CC50 were 166.7 µg/mL and 651.9 µg/mL. GG extract showed 98-100% inhibition of all four dengue serotypes at the MNTD and the IC50 values of the four serotypes ranged from 10-50 µg/mL indicating moderate pan-serotype inhibitory activity. Cytotoxicity of GG against Vero cells was low (CC50 >500 µg/mL). SI of GG extract for all four dengue serotypes were >10, indicating it had good potential as an antiviral agent. Fraction E and F had low to moderate inhibitory activity for all four serotypes and showed good potential as an antiviral agent only for dengue 4. This is the first report of significant anti-dengue viral activity of GG extract on all four dengue serotypes.
The evolution of fitness during range expansions in different dimensions
Authors: Yurii Kotsar , Matsuoka Hikaru , Tamiya Gen
Published: December 2023

We develop a set of programs – the range expansions simulation kit (RESK) – to efficiently simulate range expansions of populations on a square lattice in 1D, 2D (on a strip, and on a disk) and 3D (in a cylinder, and in a sphere). In this study, we present the simulation kit to the public and present some results of using it to simulate a population of diploid individuals with finite genome regions, each containing infinite sites. Specifically, using the programs, we calculate and analyse the temporal evolution of population fitness, as well as fitness on the expansion front, in 3D for the first time. We explore the model over different conditions, compare normalisation methods for fitness, and explore the case of radial (sphere) and axial (cylinder) expansions in 3D, which might apply in the analysis of the different real-life populations, such as viruses/bacteria inside a host, marine species in ocean environments, and potentially in future space colonization planning. In 3D expansions, we find complex spatial fluctuations in deme-average fitness values, different from those in radial 2D expansions. In axial 3D (cylinder) expansions, we determine that the highest-valued deme-average fitness lies along the axis of the expansion. We also find the fluctuation patterns of fitness in 3D cylinder expansions, similar to those previously seen in radial expansions in 2D. In radial 2D (disk) expansions, we find that the fitness of a population undergoing multiple mutations shows a smooth combination of binary segregation pictures against each of those mutations. We confirm the accumulation of deleterious mutations -- a phenomenon known as expansion load -- in all scenarios above. We present the software used in the above to the public as a Julia repository, ready to use with different functions for simulating range expansions with minimal syntax.
The mutational landscape ofBacillus subtilisconditional hypermutators shows how proofreading skews DNA polymerase error rates
Authors: Tanneur Ira , Dervyn Etienne , Guérin Cyprien , Kam King Guillaume Kon , Jules Matthieu , Nicolas Pierre
Published: December 2023

Polymerase errors during DNA replication are a major source of point mutations in genomes. The resulting rate of spontaneous mutation also depends on the counteracting activity of DNA repair mechanisms, with mutator phenotypes appearing constantly and allowing for periods of rapid evolution in nature and in the laboratory. Here, we use the Gram-positive model bacteriumBacillus subtilisto disentangle the contributions of DNA polymerase initial nucleotide selectivity, DNA polymerase proofreading, and mismatch repair (MMR) to the mutation rate. To achieve this, we constructed several conditional hypermutators with a proofreading-deficient allele ofpolCand/or a deficient allele ofmutLand performed mutation accumulation experiments. With their wide range of mutation rates and contrasting mutation profiles, these conditional hypermutators enrich theB. subtilissynthetic biology toolbox for directed evolution. Using mathematical models, we investigated how to interpret the apparent probabilities with which errors escape MMR and proofreading, highlighting the difficulties of working with counts that aggregate potentially heterogeneous mutations and with unknowns about the pathways leading to mutations in the wild-type. Aware of these difficulties, the analysis shows that proofreading prevents partial saturation of the MMR inB. subtilisand that an inherent drawback of proofreading is to skew the net polymerase error rates by amplifying intrinsic biases in nucleotide selectivity.
The ribosomal protein L22 binds theMDM4pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress
Authors: Jansen Jennifer , Bohnsack Katherine E. , Böhlken-Fascher Susanne , Bohnsack Markus T. , Dobbelstein Matthias
Published: December 2023

The tumor suppressor p53, along with its antagonists MDM2 and MDM4, represents a central integrator of stress signaling. While DNA damage is the most widely explored trigger of a p53 response, stress arising from dysbalanced assembly of ribosomes in nucleoli is also linked to p53 induction. Deletions of the gene encoding the ribosomal protein L22 (RPL22; eL22) correlate with the presence of full-lengthMDM4mRNA in human cancer, but the mechanistic basis for this phenomenon was hitherto unknown. Here we show that L22, under conditions of ribosomal and nucleolar stress, promotes the skipping of exon 6 within theMDM4pre-mRNA. Upon L22 depletion, more full-length MDM4 is maintained, independent of treatment with nucleolar stressors, leading to diminished p53 activity and enhanced cellular proliferation. Mechanistically, L22 binds to specific RNA elements within intron 6 ofMDM4that correspond to a stem-loop consensus, leading to the skipping of exon 6. This intronic RNA overlaps with the region responsible for splice regulation by ZMAT3. Targeted deletion of these intronic elements largely abolishes L22-mediated exon skipping and re-enables cell proliferation, despite nucleolar stressors such as 5-fluorouracil. L22 also governs alternative splicing of theL22L1(RPL22L1) andUBAP2LmRNAs. Thus, L22 serves as a signaling intermediate that integrates different layers of gene expression. Defects in ribosome synthesis lead to specific alternative splicing, ultimately triggering p53-mediated transcription and arresting cell proliferation.
Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition
Authors: Satouh Yuhkoh , Tatebe Takaki , Tanida Isei , Yamaguchi Junji , Uchiyama Yasuo , Sato Ken
Published: December 2023

Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to meiosis II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed ELYSAs, in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7–8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.

Summary blurb

This study describes endosomal-lysosomal organellar assembly structures in mammalian oocytes, elucidating statistical alterations in their size, distribution, and correlation with lysosomal maturation.
Objective sleep quality predicts subjective sleep ratings: a multiday observational study
Authors: Pierson-Bartel Róbert , Ujma Péter Przemyslaw
Published: December 2023

In both clinical and observational studies, sleep quality is usually assessed by subjective self-report. The literature is mixed about how accurately these self-reports track objectively (e.g. via polysomnography) assessed sleep quality, with frequent reports of a very low or no association. However, previous research on this question focused on between-subject designs, which may be confounded by trait-level variables. In the current study, we used the novel Budapest Sleep, Experiences and Traits Study (BSETS) dataset to investigate if within-subject differences in subjectively reported sleep quality are related to sleep macrostructure and quantitative EEG variables assessed using a mobile EEG headband. We found clear evidence that within-subject variations in sleep onset latency, wake after sleep onset, total sleep time, and sleep efficiency affect self-reported sleep quality in the morning. These effects were replicated if detailed sleep composition metrics (percentage and latency of specific vigilance states) or two alternative measures of subjective sleep quality are used instead. We found no effect of the number of awakenings or relative EEG delta and sigma power. Between-subject effects (relationships between individual mean values of sleep metrics and subjective sleep quality) were also found, highlighting that analyses focusing only on these may be erroneous. Our findings show that while previous investigations of this issue may have been confounded by between-subject effects, objective sleep quality is indeed reflected in subjective sleep ratings.
Functionally linked amygdala and prefrontal cortical regions are innervated by both single and double projecting cholinergic neurons
Authors: Barabás Bence , Reéb Zsófia , Papp Orsolya I. , Hájos Norbert
Published: December 2023

Cholinergic cells have been proposed to innervate simultaneously those cortical areas that are mutually interconnected with each other. To test this hypothesis, we investigated the cholinergic innervation of functionally linked amygdala and prefrontal cortical regions. First, using tracing experiments, we determined that cholinergic cells located in distinct basal forebrain (BF) areas projected to the different nuclei of the basolateral amygdala (BLA). Specifically, cholinergic cells in the ventral pallidum/substantia innominata (VP/SI) innervated the basal nucleus (BA), while the horizontal limb of the diagonal band of Broca (HDB) projected to its basomedial nucleus (BMA). In addition, cholinergic neurons in these two BF areas gave rise to overlapping innervation in the medial prefrontal cortex (mPFC), yet their axons segregated in the dorsal and ventral regions of the PFC. Using retrograde-anterograde viral tracing, we demonstrated that a portion of mPFC-projecting cholinergic neurons also innervated the BLA, especially the BA. By injecting retrograde tracers into the mPFC and BA, we found that 28% of retrogradely labeled cholinergic cells were double labeled, which typically located in the VP/SI. In addition, we found that vesicular glutamate transporter type 3 (VGLUT3)-expressing neurons within the VP/SI were also cholinergic and projected to the mPFC and BA, implicating that a part of the cholinergic afferents may release glutamate. In contrast, we uncovered that GABA is unlikely to be a co-transmitter molecule in HDB and VP/SI cholinergic neurons in adult mice. The dual innervation strategy, i.e., the existence of cholinergic cell populations with single as well as simultaneous projections to the BLA and mPFC, provides the possibility for both synchronous and independent control of the operation in these cortical areas, a structural arrangement that may maximize computational support for functionally linked regions. The presence of VGLUT3 in a portion of cholinergic afferents suggests more complex functional effects of cholinergic system in cortical structures.
Investigating genomic prediction strategies for grain carotenoid traits in a tropical/subtropical maize panel
Authors: LaPorte Mary-Francis , Suwarno Willy B. , Hannok Pattama , Koide Akiyoshi , Bradbury Peter , Crossa José , Palacios-Rojas Natalia , Diepenbrock Christine Helen
Published: December 2023

Vitamin A deficiency remains prevalent on a global scale, including in regions where maize constitutes a high percentage of human diets. One solution for alleviating this deficiency has been to increase grain concentrations of provitamin A carotenoids in maize (Zea maysssp.maysL.)—an example of biofortification. The International Maize and Wheat Improvement Center (CIMMYT) developed a Carotenoid Association Mapping panel of 380 inbred lines adapted to tropical and subtropical environments that have varying grain concentrations of provitamin A and other health-beneficial carotenoids. This project assesses the accuracy of several genomic prediction (GP) strategies for these traits (β-carotene, β-cryptoxanthin, provitamin A, lutein, and zeaxanthin) within and between four environments in Mexico. Methods employing Ridge Regression-Best Linear Unbiased Prediction, Elastic Net, or Reproducing Kernel Hilbert Spaces had high accuracy in predicting all tested provitamin A carotenoid traits and outperformed Least Absolute Shrinkage and Selection Operator. Furthermore, prediction accuracies were higher when using genome-wide markers rather than only the markers proximal to two previously identified carotenoid-related genes that have been used in marker-assisted selection, suggesting that GP is worthwhile for these traits, even though key genes have already been identified. Prediction accuracy was maintained for all traits (except lutein) in between-environment prediction. The TASSEL (Trait Analysis by aSSociation, Evolution, and Linkage) Genomic Selection plugin performed as well as other more computationally intensive methods for within-environment prediction. The findings observed herein indicate the utility of GP methods for these traits and could inform their resource-efficient implementation in biofortification breeding programs.
Drug promiscuity: problems and promises
Authors: VanDongen Antonius M.
Published: December 2023

Therapeutic drugs exert their effect by binding to a specific target protein (receptor) and altering its activity. However, all drugs have undesirable side effects, which likely result from the drug binding to other protein targets. Drug promiscuity refers to the ability of small molecule compounds to bind with high affinity to multiple proteins. This drug property is responsible for the problems caused by their side effects. But drug promiscuity also presents a promise: if a drug targets numerous proteins, each interaction may contribute to its therapeutic efficacy. The ability to target multiple genes is especially promising for medicines that treat systemic diseases, including neurological disorders and cancers, which result from gene network problems. Here, I will review both aspects of drug promiscuity and illustrate a potential strategy to move this forward using a computer modeling approach.
Timp2 loss-of-function mutation and TIMP2 treatment in murine model of NSCLC: modulation of immunosuppression and oncogenic signaling
Authors: Peeney David , Kumar Sarvesh , Singh Tej Pratap , Liu Yueqin , Jensen Sandra , Chowdhury Ananda , Coates-Park Sasha , Rich Joshua , Gurung Sadeechya , Fan Yu , Meerzaman Daoud , Stetler-Stevenson William G
Published: December 2023

Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly downregulates the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.
DORSSAA: Drug-target interactOmics Resource based on Stability/Solubility Alteration Assay
Authors: Zangene Ehsan , Gholizadeh Elham , Saei Amir Ata , Wilhelm Mathias , Jafari Mohieddin
Published: December 2023

Advancements in high-throughput techniques such as Thermal Proteome Profiling (TPP) and the high-throughput Proteome Integral Solubility Alteration (PISA) assay have revolutionized our understanding of drug-protein interactions. Despite these innovations, the absence of an integrative platform for cross-study analysis of stability and solubility alteration data represents a significant bottleneck. To address this gap, we introduce DORSSAA (Drug-target interactOmics Resource based on Stability/Solubility Alteration Assay), an interactive and expandable web-based platform for the systematic analysis and visualization of proteome stability and solubility alteration assay datasets. Currently, DORSSAA features 480,456 records spanning 37 cell lines and organisms, 39 compounds, and 40,004 potential protein targets. Through its user-friendly interface, the resource supports comparative drug-protein interaction analysis and facilitates the discovery of actionable therapeutic targets. Using two case studies of the DHFR-methotrexate interaction and drug-target interaction in the case of combinatorial therapy in Leukemia cell lines, we demonstrate DORSSAA’s utility in identifying protein-drug interactions across experimental conditions. This resource empowers researchers to accelerate drug discovery and enhance our understanding of protein behavior.

Abstract Figure
Gene module reconstruction elucidates cellular differentiation processes and the regulatory logic of specialized secretion
Authors: Wang Yiqun , Liu Jialin , Du Lucia Y , Wyss Jannik L , Farrell Jeffrey A , Schier Alexander F
Published: December 2023

During differentiation, cells become structurally and functionally specialized, but comprehensive views of the underlying remodeling processes are elusive. Here, we leverage scRNA-seq developmental trajectories to reconstruct differentiation using two secretory tissues as a model system: the zebrafish notochord and hatching gland. First, we present an approach to integrate expression and functional similarities for gene module identification, revealing dozens of gene modules representing known and newly associated differentiation processes and their temporal ordering. Second, we focused on the unfolded protein response (UPR) transducer module to study how general versus cell-type specific secretory functions are regulated. By profiling loss- and gain-of-function embryos, we found that the UPR transcription factors creb3l1, creb3l2, and xbp1 are master regulators of a general secretion program. creb3l1/creb3l2 additionally activate an extracellular matrix secretion program, while xbp1 partners with bhlha15 to activate a gland-specific secretion program. Our study offers a multi-source integrated approach for functional gene module identification and illustrates how transcription factors confer general and specialized cellular functions.
Protosequences in brain organoids model intrinsic brain states
Authors: van der Molen Tjitse , Spaeth Alex , Chini Mattia , Hernandez Sebastian , Kaurala Gregory A. , Schweiger Hunter E. , Duncan Cole , McKenna Sawyer , Geng Jinghui , Lim Max , Bartram Julian , Dendukuri Aditya , Zhang Zongren , Gonzalez-Ferrer Jesus , Bhaskaran-Nair Kiran , Blauvelt Lon J. , Harder Cole R.K. , Petzold Linda R. , Alam El Din Dowlette-Mary , Laird Jason , Schenke Maren , Smirnova Lena , Colquitt Bradley M. , Mostajo-Radji Mohammed A. , Hansma Paul K. , Teodorescu Mircea , Hierlemann Andreas , Hengen Keith B. , Hanganu-Opatz Ileana L. , Kosik Kenneth S. , Sharf Tal
Published: December 2023

Neuronal firing sequences are thought to be the basic building blocks of neural coding and information broadcasting within the brain. However, when sequences emerge during neurodevelopment remains unknown. We demonstrate that structured firing sequences are present in spontaneous activity of human and murine brain organoids andex vivoneonatal brain slices from the murine somatosensory cortex. We observed a balance between temporally rigid and flexible firing patterns that are emergent phenomena in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in primary dissociated cortical cultures. Our findings suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by an innate preconfigured architecture established during neurogenesis. These findings highlight the potential for brain organoids to further explore how exogenous inputs can be used to refine neuronal circuits and enable new studies into the genetic mechanisms that govern assembly of functional circuitry during early human brain development.
Overexpression of the WWE domain of RNF146 modulates poly-(ADP)-ribose dynamics at sites of DNA damage
Authors: Al-Rahahleh Rasha Q. , Saville Kate M. , Andrews Joel F. , Wu Zhijin , Koczor Christopher A. , Sobol Robert W.
Published: December 2023

Protein poly-ADP-ribosylation (PARylation) is a post-translational modification formed by transfer of successive units of ADP-ribose to target proteins to form poly-ADP-ribose (PAR) chains. PAR plays a critical role in the DNA damage response (DDR) by acting as a signaling platform to promote the recruitment of DNA repair factors to the sites of DNA damage that bind via their PAR-binding domains (PBDs). Several classes of PBD families have been recognized, which identify distinct parts of the PAR chain. Proteins encoding PBDs play an essential role in conveying the PAR-mediated signal through their interaction with PAR chains, which mediates many cellular functions, including the DDR. The WWE domain identifies the iso-ADP-ribose moiety of the PAR chain. We recently described the WWE domain of RNF146 as a robust genetically encoded probe, when fused to EGFP, for detection of PAR in live cells. Here, we evaluated other PBD candidates as molecular PAR probes in live cells, including several other WWE domains and an engineered macrodomain. In addition, we demonstrate unique PAR dynamics when tracked by different PAR binding domains, a finding that that can be exploited for modulation of the PAR-dependent DNA damage response.
An Interpretable Model of pre-mRNA Splicing for Animal and Plant Genes
Authors: McCue Kayla , Burge Christopher B.
Published: December 2023

Pre-mRNA splicing is a fundamental step in gene expression, conserved across eukaryotes, in which the spliceosome recognizes motifs at the 3’ and 5’ splice sites (SS), excises introns and ligates exons. SS recognition and pairing is often influenced by splicing regulatory factors (SRFs) that bind to splicing regulatory elements (SREs). Several families of sequence-specific SRFs are known to be similarly ancient. Here, we describe SMsplice, a fully interpretable model of pre-mRNA splicing that combines new models of core SS motifs, SREs, and exonic and intronic length preferences. We learn models the predict SS locations with 83-86% accuracy in fish, insects and plants, and about 70% in mammals. Learned SRE motifs include both known SRF binding motifs as well as novel motifs, and both classes are supported by genetic analyses. Our comparisons across species highlight similarities between non-mammals and a greater reliance on SREs in mammalian splicing, and increased reliance on intronic SREs in plant splicing.
Hexafluoro slows retinal degeneration and improves visual function in zebrafish models of Usher syndrome 1F
Authors: Phillips Jennifer B. , Kulis Siena , Buchner Sara H. , Fox Eric J. , Wegner Jeremy , Peirce Judy , Ivanchenko Maryna V. , Corey David P. , Arbiser Jack L. , Westerfield Monte
Published: December 2023

Usher syndrome is the leading genetic cause of deafblindness, affecting hundreds of thousands of people worldwide. The deafness can be addressed with hearing aids or cochlear implants, but there is currently no treatment for the vision loss, which is due to progressive degeneration of retinal photoreceptors. Studies in animal models of Usher syndrome have shown that photoreceptor degeneration is exacerbated by exposure to bright light, and other studies have shown that light-induced photostress reduces mitochondrial function. We previously synthesized hexafluoro and showed that it is a potent Sirt3 activator that promotes mitochondrial respiration. Here we examined the efficacy of hexafluoro as a potential therapeutic for treatment of vison loss in a zebrafish model of Usher syndrome type 1F, which exhibits early and severe vision defects along with vestibular dysfunction as seen in Usher type 1 pathology. We find that hexafluoro improves visual function, reduces photoreceptor degeneration, and protects the retina against exposure to bright light in this USH1F model.
Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure
Authors: Pavelec Caitlin M. , Young Alexander P. , Luviano Hannah L. , Orrell Emily E. , Szagdaj Anna , Poudel Nabin , Wolpe Abigail G. , Thomas Samantha H. , Yeudall Scott , Upchurch Clint M. , Okusa Mark D. , Isakson Brant E. , Wolf Matthew J. , Leitinger Norbert
Published: December 2023

Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism bothin vivoandin vitro.In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1MyHC6mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.
KMT2A oncoproteins induce epigenetic resistance to targeted therapies
Authors: Janssens Derek H. , Duran Melodie , Otto Dominik J. , Wu Weifang , Xu Yiling , Kirkey Danielle , Mullighan Charles G. , Yi Joanna S. , Meshinchi Soheil , Sarthy Jay F. , Ahmad Kami , Henikoff Steven
Published: December 2023

Chromosomal translocations involving theLysine-Methyl-Transferase-2A(KMT2A) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representativeKMT2A-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose KMT2A oncoproteins promote lineage-switching events through dynamic chromatin binding and can induce epigenetic lesions, marked by ENL, that support resistance to targeted therapies.
Age-associated aberrations of cumulus-oocyte interaction and microfilamentous structure in the zona pellucida decline female fertility
Authors: Ishikawa-Yamauchi Yu , Emori Chihiro , Mori Hideto , Endo Tsutomu , Kobayashi Kiyonori , Watanabe Yuji , Sagara Hiroshi , Nagata Takeshi , Motooka Daisuke , Ninomiya Akinori , Ozawa Manabu , Ikawa Masahito
Published: December 2023

One of the major age-related declines in female reproductive function is the reduced quantity and quality of oocytes. Here we demonstrate that structural changes in the zona pellucida (ZP) decrease fertilization rates from 34- to 38-week-old female mice, equivalent to the mid-reproductive of human females. In middle-age ovaries, the decline in the number of transzonal projections was accompanied by a decrease in cumulus cell-oocyte interactions, resulting in a deterioration of the oocyte quality. Scanning electron microscopy showed the ZP surface microfilament structure transitioning from rugged to smooth with age, leading to decreased fertilization rates due to impaired sperm binding to the ZP. Moreover, the fertilization rate of middle-age mice was restored to a comparable level to that of young mice by destabilizing the ZP in the presence of glutathione. These results suggest that the age-related structural changes in the ZP is a key for successful fertilization at reproductive age.
Decoding mTOR signalling heterogeneity in the tumour microenvironment using multiplexed imaging and graph convolutional networks
Authors: Zuhair Razan , Eastwood Mark , Jones Megan , Cross Amy , Hester Joanna , Issa Fadi , Ginty Fiona , Sailem Heba
Published: December 2023

Evaluating the contribution of the tumour microenvironment (TME) in tumour progression has proven a complex challenge due to the intricate interactions within the TME. Multiplexed imaging is an emerging technology that allows concurrent assessment of multiple of these components simultaneously. Here we utilise a highly multiplexed dataset of 61 markers across 746 colorectal tumours to investigate how complex mTOR signalling in different tissue compartments influences patient prognosis. We found that the signalling of mTOR pathway can have heterogeneous activation patterns in tumour and immune compartments which correlate with patient prognosis. Using graph neural networks, we determined the most predictive features of mTOR activity in immune cells and identified relevant cellular subpopulations. We validated our observations using spatial transcriptomics data analysis in an independent patient cohort. Our work provides a framework for studying complex cell signalling and reveals important insights for developing mTOR-based therapies.
The professional competence of faculty members from the students’ perspective at Kuwait University and Palestine Technical University Kadoorie
Authors: Obied Asem , Alajmi Abdullah
Published: December 2023

Purpose

The study aimed at identifying the degree of professional competence of faculty members from the students’ perspective at Kuwait and Palestine Technical University Kadoorie, and identifying the effect of the variables of gender and academic year.

Design/methodology/approach

The researchers developed a 24-item questionnaire and administered it to 115 students each from Kuwait (male: 57, female: 58) and Palestine Technical University Kadoorie (male: 21, female: 94). The study used a descriptive approach to analyze the collected data.

Findings

According to the students' perspective, the average professional competence of faculty members at Kuwait University is 2.74 for the teaching competencies, 2.29 for the technology competencies, 2.65 for the evaluation competencies and 2.71 for the human competencies. Similarly, at Palestine Technical University Kadoorie, the mean of the professional competencies of faculty members from the students' perspective is 2.31 for the teaching competencies, 1.96 for the technology competencies, 2.24 for the evaluation competencies and 2.34 for the human competencies. There were significant differences in the degree of professional competence at Kuwait and Palestine Technical University Kadoorie due to the gender of all domains in favor of females. There were significant differences in the degree of professional competence in Kuwait due to the academic year of the technology domain between the first year and second year, in favor of the second year. There were significant differences due to the variable of the academic year of the human domain between the first year and the third year, in favor of the third year. There were significant differences in the degree of professional competence at Palestine Technical University Kadoorie due to the academic year of the technology domain (second, third, fourth year and more) and second year, in favor of (the second year). There were significant differences due to the academic year of the human domain between the first and second year, in favor of second year.

Originality/value

The authors hope that their findings will inspire further research in this area and help universities to better support their faculty members and improve student outcomes.
Multi-view fuzzy C-means clustering with kernel metric and local information for color image segmentation
Authors: Cai Xiumei , Yang Xi , Wu Chengmao
Published: December 2023

Purpose

Multi-view fuzzy clustering algorithms are not widely used in image segmentation, and many of these algorithms are lacking in robustness. The purpose of this paper is to investigate a new algorithm that can segment the image better and retain as much detailed information about the image as possible when segmenting noisy images.

Design/methodology/approach

The authors present a novel multi-view fuzzy c-means (FCM) clustering algorithm that includes an automatic view-weight learning mechanism. Firstly, this algorithm introduces a view-weight factor that can automatically adjust the weight of different views, thereby allowing each view to obtain the best possible weight. Secondly, the algorithm incorporates a weighted fuzzy factor, which serves to obtain local spatial information and local grayscale information to preserve image details as much as possible. Finally, in order to weaken the effects of noise and outliers in image segmentation, this algorithm employs the kernel distance measure instead of the Euclidean distance.

Findings

The authors added different kinds of noise to images and conducted a large number of experimental tests. The results show that the proposed algorithm performs better and is more accurate than previous multi-view fuzzy clustering algorithms in solving the problem of noisy image segmentation.

Originality/value

Most of the existing multi-view clustering algorithms are for multi-view datasets, and the multi-view fuzzy clustering algorithms are unable to eliminate noise points and outliers when dealing with noisy images. The algorithm proposed in this paper has stronger noise immunity and can better preserve the details of the original image.
The struggle of sensor-based digital servitization: analysis and perspectives for organizational digital transformation in SMEs
Authors: Trabert Thomas , Doerr Luca , Lehmann Claudia
Published: December 2023

Purpose

The organizational digital transformation (ODT) in companies presents small and medium-sized enterprises (SMEs) – who remain at the beginning of this transformation – with the challenge of offering digital services based on sensor technologies. Against this backdrop, the present paper identifies ways SMEs can enable digital servitization through sensor technology and defines the possible scope of the organizational transformation process.

Design/methodology/approach

Around 21 semi-structured interviews were conducted with experts from different hierarchical levels across the German manufacturing SME ecosystem. Using the Gioia methodology, fields of action were identified by focusing on influencing factors and opportunities for developing these digital services to offer them successfully in the future.

Findings

The complexity of existing sensor offerings must be mastered, and employees' (data) understanding of the technology has increased. Knowledge gaps, which mainly relate to technical and organizational capabilities, must be overcome. The potential of sensor technology was considered on an individual, technical and organizational level. To enable the successful implementation of service offerings based on sensor technology, all relevant stakeholders in the ecosystem must network to facilitate shared value creation. This requires standardized technical and procedural adaptations and is an essential prerequisite for data mining.

Originality/value

Based on this study, current problem areas were analyzed, and potentials that create opportunities for offering digital sensor services to manufacturing SMEs were identified. The identified influencing factors form a conceptual framework that supports SMEs' future development of such services in a structured manner.
Supply chain resilience as a system quality: survey-based evidence from multiple industries
Authors: Gruchmann Tim , Stadtfeld Gernot M. , Thürer Matthias , Ivanov Dmitry
Published: December 2023

Purpose

Experiencing more frequent, system-wide disruptions, such as pandemics and geopolitical conflicts, supply chains can be largely destabilized by a lack of materials, services or components. Supply chain resilience (SCRES) constitutes the network ability to recover after and survive during such unexpected events. To enhance the understanding of SCRES as a system-wide quality, this study tests a comprehensive SCRES model with data from multiple industries.

Design/methodology/approach

The study proposes a theoretical framework conceptualizing SCRES as system quality, extending the classical proactive/reactive taxonomy by multiple system states consisting of the supply system properties, behaviors and responses to disruptions. Underlying hypotheses were tested using an online survey. The sample consists of 219 responses from German industries. Maximum likelihood structural equation modeling (ML-SEM) and moderation analysis were used for analyzing the survey data. The study was particularly designed to elaborate on supply chain theory.

Findings

Two pathways of parallel SCRES building were identified: proactive preparedness via anticipation and reactive responsiveness via agility. Both system responses are primarily built simultaneously rather than successively. The present study further provides empirical evidence on the central role of visibility and velocity in achieving comprehensive SCRES, while flexibility only exerts short-term support after a disruption. The study additionally points to potential “spillover effects” such as the vital role of proactive SCRES in achieving reactive responsiveness.

Originality/value

The present study confirms and expands existing theories on SCRES. While stressing the multidimensionality of SCRES, it theorizes the (inter-)temporal evolution of a system and offers practical guidelines for SCRES building in various industrial contexts. It thus supports the transformation toward more resilient and viable supply chains, contributing to the increasing efforts of middle-range theory building to achieve an overarching theory. The study also points to potential future research avenues.
Subjective assessment of women's economic welfare in public sector organizations of Mardan, Northern Pakistan
Authors: Begum Nazia , Tariq Muhammad , Jehan Noor , Khan Farah
Published: December 2023

Purpose

The measurement of women's economic welfare and exploring its underlying factors have been undervalued in the context of Khyber Pakhtunkhwa, Pakistan. This study addressed this gap by focusing on assessing women's subjective economic welfare and its socioeconomic and cultural determinants in the education and health sectors within Mardan, Northern Pakistan.

Design/methodology/approach

The study used stratified random sampling techniques for the selection of sample respondents and collected data through a well-structured questionnaire. To measure women’s economic welfare, the study utilizes Lorenz curves, the Gini index, the Sen Social Welfare function and an individual's gross monthly income. Furthermore, the ordinary least squares method was utilized to analyze the determinants of economic welfare.

Findings

The findings show greater income inequality and a lower welfare level for women in the education sector compared to the health sector. Likewise, the study identifies several key determinants, such as age, educational qualification, job experience, respect for working women, outside and work-place problems and the suffering of family members of working women for their economic well-being.

Originality/value

This study makes valuable contributions to the literature by focusing on the cultural perspective of Pakhtun women in Mardan and providing a context-specific understanding of subjective economic welfare. Additionally, the authors collected first-hand data, which gave an original outlook on working women's current economic welfare level. Furthermore, this study undertakes a comparative analysis of working women's welfare in the health and education sectors. This comparison offers a more accurate portrayal of the challenges and opportunities specific to these occupations.

Peer review

The peer-review history for this article is available at: https://publons.com/publon/10.1108/IJSE-04-2023-0246
Toward sustainable governance with participatory budgeting
Authors: Sinervo Lotta-Maria , Bartocci Luca , Lehtonen Pauliina , Ebdon Carol
Published: December 2023

Purpose

Sustainability is a pressing challenge of governance and public financial management. One key element of sustainable governance is the role of citizens. Participatory budgeting (PB) is a participatory tool with which citizens can influence public administration. PB is a democratic process that grants people real power over real money and it has spread around the world. This special issue explores the role of PB in the context of sustainable governance. In this editorial, the authors aim to approach PB as a form of sustainable governance.

Design/methodology/approach

In this editorial, the authors collaborate in the analysis of how PB is implicated in the public management of complex social, economic and ecological issues. The authors identify key dimensions of internal and external sustainability based on prior research. The authors approach these dimensions as an internal–external nexus of sustainable governance in which organizational and financial sustainability are the internal dimensions and socio-political and environmental sustainability are the external dimensions.

Findings

Even though PB can be seen as one tool for citizen participation, it has the potential to foster sustainability in multiple ways. PB, as a form of sustainable governance, requires a financially and administratively sustainable organizational process that results in the institutionalization of PB. It also includes thorough consideration of socio-political and environmental sustainability impacts of PB.

Originality/value

Academics are actively studying PB from various perspectives. However, most of this work has approached PB from the viewpoints of design and results of PB, and less is known about its institutional settings. PB has not yet been adequately studied in the context of sustainability, and there is a need to scrutinize PB as a form of sustainable governance.