bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Inflammatory Bowel Disease and Pediatric Onset Multiple Sclerosis With Ocrelizumab and Ustekinumab in a JC-virus Positive Adolescent
Authors: Lambert-Jenkins Kristin , Rossman Ian , Watson Kevin L
Published: June 2022

Inflammatory bowel disease (IBD) and multiple sclerosis (MS) are known to co-occur. Many disease modifying therapies for MS may exacerbate IBD and several carry risk of progressive multifocal leukoencephalopathy in JC-virus (JCV) positive patients. Some biologics used for IBD can exacerbate MS. These factors make comanagement of these diseases difficult. We report a 17-year-old female who presented with right leg weakness and paresthesia and was diagnosed with pediatric onset MS (POMS). She then had worsening abdominal pain and diarrhea, accompanied by weight loss, and was subsequently diagnosed with Crohn’s disease. She was weakly JCV positive, so a short trial of natalizumab was initiated, which controlled her POMS well but not her IBD. Ustekinumab and ocrelizumab were initiated and achieved remission of both diseases. In the absence of established treatment guidelines, we recommend considering this combination of therapies for cases where standard treatment modalities are not viable options.
Elevated CD4+ T-cell glucose metabolism in HIV+ women with diabetes mellitus
Authors: Butterfield Tiffany R. , Hanna David B. , Kaplan Robert C. , Xue Xiaonan , Kizer Jorge R. , Durkin Helen G. , Kassaye Seble G. , Nowicki Marek , Tien Phyllis C. , Topper Elizabeth T. , Floris-Moore Michelle A. , Titanji Kehmia , Fischl Margaret A. , Heath Sonya , Palmer Clovis S. , Landay Alan L. , Anzinger Joshua J.
Published: June 2022

Objective:

Immune dysfunction and chronic inflammation are characteristic of HIV infection and diabetes mellitus, with CD4+ T-cell metabolism implicated in the pathogenesis of each disease. However, there is limited information on CD4+ T-cell metabolism in HIV+ persons with diabetes mellitus. We examined CD4+ T-cell glucose metabolism in HIV+ women with and without diabetes mellitus.

Design:

A case–control study was used to compare CD4+ T-cell glucose metabolism in women with HIV with or without diabetes mellitus.

Methods:

Nondiabetic (HIV+DM−, N = 20) or type 2 diabetic HIV+ women with (HIV+DM+, N = 16) or without (HIV+DMTx+, N = 18) antidiabetic treatment were identified from the WIHS and matched for age, race/ethnicity, smoking status and CD4+ cell count. CD4+ T-cell immunometabolism was examined by flow cytometry, microfluidic qRT-PCR of metabolic genes, and Seahorse extracellular flux analysis of stimulated CD4+ T cells.

Results:

HIV+DM+ displayed a significantly elevated proportion of CD4+ T cells expressing the immunometabolic marker GLUT1 compared with HIV+DMTx+ and HIV+DM− (P = 0.04 and P = 0.01, respectively). Relative expression of genes encoding key enzymes for glucose metabolism pathways were elevated in CD4+ T cells of HIV+DM+ compared with HIV+DMTx+ and HIV+DM−. T-cell receptor (TCR)-activated CD4+ T cells from HIV+DM+ showed elevated glycolysis and oxidative phosphorylation compared with HIV+DM−.

Conclusion:

CD4+ T cells from HIV+DM+ have elevated glucose metabolism. Treatment of diabetes mellitus among women with HIV may partially correct CD4+ T-cell metabolic dysfunction.
Fluoxetine reduces organ injury and improves motor function after traumatic brain injury in mice
Authors: Weaver Jessica L. , Eliceiri Brian , Costantini Todd W.
Published: June 2022

BACKGROUND

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in trauma patients worldwide. Brain injury is associated with significant inflammation, both within the brain and in the peripheral organs. This inflammatory response in TBI leads to a secondary injury, worsening the effects of the original brain injury. Serotonin is also linked to inflammation in the intestine and inflammatory bowel disease, but its role in the gut-brain axis is not known. We hypothesized that using fluoxetine to block serotonin reuptake would reduce organ inflammation and improve outcomes after TBI.

METHODS

C57/B6 mice were given a severe TBI using a controlled cortical impact. To measure intestinal permeability, a piece of terminal ileum was resected, the lumen was filled with 4-kDa fluorescein isothiocyanate (FITC)-dextran, and the ends were tied. The intestinal segment was submerged in buffer and fluorescence in the buffer measured over time. To measure lung permeability, 70-kDa FITC-dextran is injected retro-orbitally. Thirty minutes later, the left lung was homogenized and the fluorescence was measured. To measure performance on the rota-rod, mice were placed on a spinning rod, and the time to fall off was measured. Those treated with fluoxetine received a single dose of 5 mg/kg via intraperitoneal injection immediately after injury.

RESULTS

Traumatic brain injury was associated with an increase in intestinal permeability to FITC-dextran, increased lung vascular permeability, and worse performance on the rota-rod. Fluoxetine significantly reduced lung and intestinal permeability after TBI and improved performance on the rota-rod after TBI.

CONCLUSION

Use of fluoxetine has the potential to reduce lung injury and improve motor coordination in severe TBI patients. Further study will be needed to elucidate the mechanism behind this effect.
In vivoassessment of mechanical properties during axolotl development and regeneration using confocal Brillouin microscopy
Authors: Riquelme-Guzmán Camilo , Beck Timon , Edwards-Jorquera Sandra , Schlüßler Raimund , Müller Paul , Guck Jochen , Möllmert Stephanie , Sandoval-Guzmán Tatiana
Published: June 2022

In processes such as development and regeneration, where large cellular and tissue rearrangements occur, cell fate and behaviour are strongly influenced by tissue mechanics. While most well-established tools probing mechanical properties require an invasive sample preparation, confocal Brillouin microscopy captures mechanical parameters optically with high resolution in a contact-free and label-free fashion. In this work, we took advantage of this tool and the transparency of the highly regenerative axolotl to probe its mechanical propertiesin vivofor the first time. We mapped the Brillouin frequency shift with high resolution in developing limbs and regenerating digits, the most studied structures in the axolotl. We detected a gradual increase in the cartilage Brillouin frequency shift, suggesting decreasing tissue compressibility during both development and regeneration. Moreover, we were able to correlate such an increase with the regeneration stage, which was undetected with fluorescence microscopy imaging. The present work evidences the potential of Brillouin microscopy to unravel the mechanical changes occurringin vivoin axolotls, setting the basis to apply this technique in the growing field of epimorphic regeneration.
Efficient direct and limited environmental transmission of SARS-CoV-2 lineage B.1.22 in domestic cats
Authors: Gerhards Nora M. , Gonzales Jose L. , Vreman Sandra , Ravesloot Lars , van den Brand Judith M.A. , Doekes Harmen P. , Egberink Herman F. , Stegeman Arjan , Oreshkova Nadia , van der Poel Wim H.M. , de Jong Mart C.M.
Published: June 2022

Susceptibility of domestic cats for infection with SARS-CoV-2 has been demonstrated by several experimental studies and field observations. We performed an extensive study to further characterize transmission of SARS-CoV-2 between cats, both by direct contact as well as by indirect contact. To that end, we estimated the transmission rate parameter and the decay parameter for infectivity in the environment. Using four groups of pair-transmission experiment, all donor (inoculated) cats became infected, shed virus and seroconverted, while three out of four direct contact cats got infected, shed virus and two of those seroconverted. One out of eight cats exposed to a SARS-CoV-2-contaminated environment became infected but did not seroconvert. Statistical analysis of the transmission data gives a reproduction number R0 of 2.18 (95% CI: (0.92-4.08), a transmission rate parameter β of 0.23 day-1 (95% CI: 0.06-0.54), and a virus decay rate parameter μ of 2.73 day-1 (95% CI: 0.77-15.82). These data indicate that transmission between cats can be sustained (R0>1), however, infectiousness of a contaminated environment decays rapidly (mean duration of infectiousness 1/2.73 days). Infections of cats via exposure to a SARS-CoV-2-contaminated environment cannot be excluded if cats are exposed shortly after contamination.
Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media
Authors: Zhou Qi , Schirrmann Kerstin , Doman Eleanor , Chen Qi , Singh Naval , Selvaganapathy P. Ravi , Bernabeu Miguel O. , Jensen Oliver E. , Juel Anne , Chernyavsky Igor L. , Krüger Timm
Published: June 2022

The dynamics of blood flow in the smallest vessels and passages of the human body, where the cellular character of blood becomes prominent, plays a dominant role in the transport and exchange of solutes. Recent studies have revealed that the micro-haemodynamics of a vascular network is underpinned by its interconnected structure, and certain structural alterations such as capillary dilation and blockage can substantially change blood flow patterns. However, for extravascular media with disordered microstructure (e.g., the porous intervillous space in the placenta), it remains unclear how the medium’s structure affects the haemodynamics. Here, we simulate cellular blood flow in simple models of canonical porous media representative of extravascular biological tissue, with corroborative microfluidic experiments performed for validation purposes. For the media considered here, we observe three main effects: first, the relative apparent viscosity of blood increases with the structural disorder of the medium; second, the presence of red blood cells (RBCs) dynamically alters the flow distribution in the medium; third, increased structural disorder of the medium can promote a more homogeneous distribution of RBCs. Our findings contribute to a better understanding of the cellscale haemodynamics that mediates the relationship linking the function of certain biological tissues to their microstructure.
Anamnestic Humoral Correlates of Immunity Across SARS-CoV-2 Variants of Concern
Authors: McNamara Ryan P. , Maron Jenny S. , Bertera Harry L. , Boucau Julie , Roy Vicky , Barczak Amy K. ,   The Positives Study Staff, Franko Nicholas , Li Jonathan Z. , McLellan Jason S. , Siedner Mark J. , Lemieux Jacob E. , Chu Helen Y. , Alter Galit
Published: June 2022

While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across VoCs, including the Delta and more distant Omicron variant of concern (VoC), remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals recently infected with either the Delta or Omicron VoC. While limited acute N-terminal domain and RBD-specific immune expansion was observed following breakthrough, a significant immunodominant expansion of opsinophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed 1 week after breakthrough infection. This S2-specific functional humoral response continued to evolve over 2-3 weeks following both Delta and Omicron breakthrough infection, targeting multiple VoCs and common coronaviruses. These responses were focused largely on the fusion peptide 2 and heptad repeat 1, both associated with enhanced rates of viral clearance. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the control of SARS-CoV-2 infection, across VOCs, and thus humoral response linked to virus attenuation can guide next-generation generation vaccine boosting approaches to confer broad protection against future SARS-CoV-2 VoCs.
α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation
Authors: Vadukul Devkee M. , Papp Marcell , Thrush Rebecca J. , Wang Jielei , Jin Yiyun , Arosio Paolo , Aprile Francesco A.
Published: June 2022

An increasing number of cases where amyloids of different proteins are found in the same patient are being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer’s and Parkinson’s diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we show that soluble species containing amyloid-β can induce the aggregation of α-synuclein. Fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated, but not as part of the core of the fibrils. Importantly, by global kinetic analysis, we found that the aggregation of α-synuclein under these conditions occurs via heterogeneous primary nucleation, triggered by soluble aggregates containing amyloid-β.
Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia
Authors: Iseppon Federico , Luiz Ana P. , Linley John E. , Wood John N.
Published: June 2022

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent NaV1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin and other neuropathic insults. This event has been causally linked to the development of cold and mechanical allodynia. Pregabalin is an anti-epileptic and analgesic drug that acts through a calcium channel α2δ-1 subunit to lower neurotransmitter release. Recent data also suggest pregabalin can act on NMDA receptors and other proteins, but the site of analgesic action has been considered to be the central nervous system. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 driven by a Pirt promoter in all sensory neurons. We found that in mice treated with oxaliplatin, intravenous injection of pregabalin significantly decreased cold allodynia. Interestingly, pregabalin also decreased the number of sensory neurons responding to cold nociceptive stimuli by altering their excitability and their temperature thresholds. These silenced neurons are medium/large cells responding to both painful mechanical and cold stimuli, corresponding to the “silent” cold sensors that become active in numerous neuropathic pain models. Deletion of α2δ-1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neuron unmasked by oxaliplatin. Taken together, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of silent cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.

Abbreviated Summary

Iseppon et al. report a novel, peripheral effect of pregabalin on oxaliplatin-dependent cold allodynia. The drug exerts its effect by silencing a specific sub-population of neurons responding to cold and mechanical stimuli in the dorsal root ganglion, and this effect is dependent on the α2δ-1 subunit of voltage-gated calcium channels.
Endogenous Rab38 regulates LRRK2’s membrane recruitment and substrate Rab phosphorylation in melanocytes
Authors: Unapanta Alexandra , Shavarebi Farbod , Porath Jacob , Balen Carson , Nguyen Albert , Tseng Josh , Shen Yiyi , Liu Michelle , Lis Pawel , Di Pietro Santiago M. , Hiniker Annie
Published: June 2022

Point mutations in LRRK2 cause Parkinson’s Disease and augment LRRK2’s kinase activity. However, cellular pathways that enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions. Here we identify Rab38 as a novel physiological regulator of LRRK2. In mouse melanocytes, which express high levels of Rab38, Rab32, and Rab29, knockdown of Rab38 but not Rab32 or Rab29 decreases phosphorylation of multiple LRRK2 substrates, including Rab10 and Rab12, by both exogenous and endogenous LRRK2. In B16-F10 mouse melanoma cells, Rab38 drives LRRK2 membrane association, and overexpressed kinase-active but not kinase-inactive LRRK2 shows striking pericentriolar recruitment, which is dependent on the presence of endogenous Rab38 but not Rab32 or Rab29. Deletion or mutation of LRRK2 at the Rab38 binding site in the N-terminal armadillo domain decreases LRRK2 membrane association, pericentriolar recruitment, and ability to phosphorylate Rab10. Consistently, overexpression of LRRK2350-550, a fragment that encompasses the Rab38 binding site, blocks endogenous LRRK2’s phosphorylation of Thr73-Rab10. Finally, disruption of BLOC-3, the guanine nucleotide exchange factor for Rab38 and 32, inhibits Rab38’s regulation of LRRK2. In sum, our data identify Rab38 as a physiologic regulator of LRRK2 function and lend support to a model in which LRRK2 plays a central role in Rab GTPase coordination of vesicular trafficking.
Type III CRISPR–Cas provides resistance against nucleus-forming jumbo phages via abortive infection
Authors: Mayo-Muñoz David , Smith Leah M. , Garcia-Doval Carmela , Malone Lucia M. , Harding Kate R. , Jackson Simon A. , Hampton Hannah G. , Fagerlund Robert D. , Gumy Laura F. , Fineran Peter C.
Published: June 2022

Bacteria have diverse defences against phages. In response, jumbo phages evade multiple DNA-targeting defences by protecting their DNA inside a nucleus-like structure. We previously demonstrated that RNA-targeting type III CRISPR–Cas systems provide jumbo phage immunity by recognising viral mRNA exported from the nucleus for translation. Here, we demonstrate that recognition of phage mRNA by the type III system activates a cyclic triadenylate-dependent accessory nuclease, NucC. Although unable to access phage DNA in the nucleus, NucC degrades the bacterial chromosome, triggers cell death, and disrupts phage replication and maturation. Hence, type III-mediated jumbo phage immunity occurs via abortive infection, with suppression of the viral epidemic protecting the population. We further show that type III systems targeting jumbo phages have diverse accessory nucleases, including RNases that provide immunity. Our study demonstrates how type III CRISPR–Cas systems overcome the inaccessibility of jumbo phage DNA to provide robust immunity.
Paralog dispensability shapes homozygous deletion patterns in tumor genomes
Authors: De Kegel Barbara , Ryan Colm J.
Published: June 2022

Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness – they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of >10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non-essential paralogs. Overall our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable.
Clean-PIE: a novel strategy for efficiently constructing precise circRNA with thoroughly minimized immunogenicity to direct potent and durable protein expression
Authors: Qiu Zonghao , Hou Qiangbo , Zhao Yang , Zhu Jiafeng , Zhai Mengting , Li Daolei , Li Yi , Liu Chunxi , Li Na , Cao Yifei , Yang Jiali , Sun Zhenhua , Zuo Chijian
Published: June 2022

Translatable circular RNAs (circRNAs) are emerging as a crucial molecular format for transient protein expression, with high potential to be an alternative for linear mRNA to reshape the landscape of mRNA pharmaceutical industry. Canonical Anabaena permuted intron-exon (Ana PIE) format that developed by ORNA is an efficient method for RNA circularization, and the engineered circRNAs direct supreme protein expression in eukaryotic cells. However, recent studies revealed that this method may unavoidably result in a remain of immunogenicity in the circRNA products, albeit after thorough RNA purification. In the current study, we develop a novel strategy for efficient generation of circRNA, via the permuted T4Td introns mediated autocatalytically ribozymatic reaction mediated ligation of the flanking segment sequences that concealing in ORF or translation initiation sequence (normally equal to IRES). This strategy universally realizes around 90% circularization effectivity, and the circRNA products can be purified to around 90% purity by our new purification method, and presented thoroughly minimized immunogenicity, thus is termed “Clean-PIE”. The purified circRNAs are found to direct potent and durable expression of various proteins in vitro and in vivo. The partly purified Fluc circRNA by HPLC-SEC was found to direct Fluc expression in muscle for no less than 20 days. The highly purified circRNA exhibits much stronger protein expression in vitro and in vivo, and presumed a longer duration. Additionally, the scale-up of RNA circularization with the RNA precursors from 1 L transcription revealed high circularization effectivity (around 90%) and a high productivity of the final circRNA products. Collectively, Clean-PIE is a novel circRNA platform that possesses high circularization effectivity, enabled high RNA purity and thoroughly minimized immunogenicity, as well as scaling-up accessibility and directing extreme durability of protein expression, thus has the potential to develop advanced RNA vaccines and therapeutics in pharmaceutical industrial scale.
Surface productivity gradients govern changes in abundance and physiological status of deep ocean prokaryotes across the tropical and subtropical Atlantic
Authors: Gómez-Letona Markel , Arístegui Javier , Hernández-Hernández Nauzet , Pérez-Lorenzo María , Álvarez-Salgado Xosé Antón , Teira Eva , Sebastián Marta
Published: June 2022

Prokaryotes represent a major fraction of marine biomass and play a key role in the global carbon cycle. We studied the vertical profiles (from surface down to the bathypelagic realm) of abundance, cytometric signatures, and activity of prokaryotic communities along a productivity gradient in the subtropical and tropical Atlantic to assess whether there is a vertical linkage between surface productivity regimes and deep ocean prokaryotic communities. We found that latitudinal changes in the vertical patterns of cytometric variables were coupled with surface productivity: higher prokaryotic abundances and viabilities, and smaller cell sizes were observed below highly productive surface waters, an effect reaching down to the bathypelagic layer. On the contrary, leucine uptake rates in deep waters showed no clear relationship with surface productivity. Changes in resource and energy allocation to growth vs. maintenance in hostile environments, cell-size-dependent metabolic requirements and variability in leucine to carbon conversion may all be part of the array of factors involved in controlling prokaryotic activity patterns that were measured. Our work adds to the recent findings that highlight the importance of vertical connectivity for prokaryotic communities in the dark ocean.
Dynamic Compartmentalisation of Intracellular Sodium in collecting duct cells
Authors: Assmus A. , Mullins L. , Sherborne C. , Peter A. , Early J. , Claeyssens F. , Haycock J. W. , Hunter R. , Mullins J. J.
Published: June 2022

In Principal cells (PC) of the cortical collecting duct (CCD), the highly regulated and coordinated reabsorption of sodium occurs through the epithelial sodium channel (ENaC) at the apical membrane and Na/K ATPase at the basolateral membrane. However, it is not known how sodium ions (Na+) are transported across the cell. We investigated intracellular transport in mCCDcl1 cells using a fluorescent sodium dye, CoroNa Green AM. Dye uptake was stimulated by aldosterone, blocked by amiloride (an ENaC inhibiter), and basolateral transport was prevented by ouabain (an Na/K ATPase blocker) thus validating the dye’s apparently faithful replication of sodium transport. Cells exhibited a consistent pattern of sodium-containing vesicles, of various sizes, surrounded by cytoskeleton and lipid membrane. While the smallest vesicles (∼0.5μm) co-stained with lysotracker, larger vesicles (up to 6.4μm) did not co-stain with either lysosomal- or mitochondrial-specific dyes and appeared to have internal structure, suggesting that they were multivesicular bodies. Time-lapse imaging showed a subset of these multivesicular bodies release or take up sodium dye in a controlled manner. Our novel data suggest that intracellular sodium compartmentalisation is highly regulated and offer new insights into intracellular sodium dynamics in the collecting duct, revealing potential new targets for control of sodium homeostasis.

New and Noteworthy

The article shows for the first time, to our knowledge, intracellular sodium transport mechanism in mCCDcl1 cells in the form of dynamic vesicular bodies. These structures offer new targets for the regulation of sodium homeostasis and transport in the kidney collecting duct, with wider implications for blood pressure regulation.
Analysis of pre-symptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration
Authors: Garcia-Vaquero Marina , Heim Marjorie , Flix Barbara , Pereira Marcelo , Palin Lucile , Marques Tânia M. , Pinto Francisco R. , de Las Rivas Javier , Voigt Aaron , Besse Florence , Gama-Carvalho Margarida
Published: June 2022

Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown. Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, our integrative approach revealed they exert a concerted effect on protein functional modules, acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes. The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.
Theileria annulata histone deacetylase 1 (TaHDAC1) initiates schizont to merozoite stage conversion
Authors: Tajeri Shahin , Momeux Laurence , Saintpierre Benjamin , Mfarrej Sara , Chapple Alexander , Mourier Tobias , Shiels Brian , Ariey Frédéric , Pain Arnab , Langsley Gordon
Published: June 2022

A fungal metabolite, FR235222, specifically inhibits a histone deacetylase of the apicomplexan parasite Toxoplasma gondii and TgHDAC3 has emerged as a key factor regulating developmental stage transition in this species. Here, we exploited FR235222 to ask if changes in histone acetylation regulate developmental stage transition of Theileria annulata, another apicomplexan species. We found that FR235222 treatment of T. annulata-infected transformed leukocytes induced a proliferation arrest. The blockade in proliferation was due to drug-induced conversion of intracellular schizonts to merozoites that lack the ability to maintain host leukocyte cell division. Induction of merogony by FR235222 leads to an increase in expression of merozoite-marker (rhoptry) proteins. RNA-seq of FR235222-treated T. annulata-infected B cells identified deregulated expression of 468 parasite genes including a number encoding parasite ApiAP2 transcription factors. Thus, similar to T. gondii, FR235222 inhibits T. annulata HDAC (TaHDAC1) activity and places parasite histone acetylation as a major regulatory event of the transition from schizonts to merozoites.
Cancer cells survival is dependent on the lincRNA JUNI
Authors: Kumar Vikash , Sabaté-Cadenas Xavier , Soni Isha , Stern Esther , Carine Vias , Ginsberg Doron , Dodel Martin , Mardakheh Faraz K. , Shkumatava Alena , Shaulian Eitan
Published: June 2022

Identification of key factors for cellular survival is a basis for therapy. We identified JUNI (linc01135) as a stress-regulated lncRNA, essential for cell survival and implicated in cancer. Besides regulating c-Jun expression we demonstrate c-Jun-independent, robust requirement for cell survival. Analysis of median survival of cancer patients suffering from various types of cancer reveals correlations of JUNI expression levels with alterations in patients’ survival. JUNI’s antagonistic interaction with DUSP14, a negative regulator of the JNK pathway, underlies the regulation of c-Jun and partial effects on cellular survival. Consistently, DUSP14 expression is coherently inversely-correlated with the survival of patients suffering from the same types of cancer. Our data suggests that JUNI is a novel master regulator of cell fate.

JUNI is a novel regulator of cell survival, JNK activation and c-Jun expression, implicated in survival of cancer patients
A fluorescent perilipin 2 knock-in mouse model visualizes lipid droplets in the developing and adult brain
Authors: Madsen Sofia , Delgado Ana C. , Cadilhac Christelle , Battison Fabrice , Maillard Vanille , Magrinelli Elia , Jabaudon Denis , Telley Ludovic , Doetsch Fiona , Knobloch Marlen
Published: June 2022

Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by endogenously labelling the LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are present in various cells in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we show that LDs are abundant during brain development and can be visualized using live-imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2.
Identification of a guanine-specific pocket in the protein N of SARS-CoV-2
Authors: Ciges-Tomas J. Rafael , Franco María Luisa , Vilar Marçal
Published: June 2022

The SARS-CoV-2 nucleocapsid protein (N) is responsible for RNA binding. Here we report the crystal structure of the C-terminal domain (NCTD) in open and closed conformations and in complex with guanine triphosphate, GTP. The crystal structure and biochemical studies reveals a specific interaction between the guanine, a nucleotide enriched in the packaging signals regions of coronaviruses, and a highly conserved tryptophan residue (W330). In addition, EMSA assays with SARS-CoV-2 derived RNA hairpin loops from a putative viral packaging sequence showed the preference interaction of the N-CTD to RNA oligonucleotides containing G and the loss of the specificity in the mutant W330A. Here we propose that this interaction may facilitate the viral assembly process. In summary we have identified a specific guanine-binding pocket in the N protein that may be used to design viral assembly inhibitors.
Design of ensemble recurrent model with stacked fuzzy ARTMAP for breast cancer detection
Authors: Das Abhishek , Mohanty Mihir Narayan
Published: June 2022

Purpose

In time and accurate detection of cancer can save the life of the person affected. According to the World Health Organization (WHO), breast cancer occupies the most frequent incidence among all the cancers whereas breast cancer takes fifth place in the case of mortality numbers. Out of many image processing techniques, certain works have focused on convolutional neural networks (CNNs) for processing these images. However, deep learning models are to be explored well.

Design/methodology/approach

In this work, multivariate statistics-based kernel principal component analysis (KPCA) is used for essential features. KPCA is simultaneously helpful for denoising the data. These features are processed through a heterogeneous ensemble model that consists of three base models. The base models comprise recurrent neural network (RNN), long short-term memory (LSTM) and gated recurrent unit (GRU). The outcomes of these base learners are fed to fuzzy adaptive resonance theory mapping (ARTMAP) model for decision making as the nodes are added to the F_2ˆa layer if the winning criteria are fulfilled that makes the ARTMAP model more robust.

Findings

The proposed model is verified using breast histopathology image dataset publicly available at Kaggle. The model provides 99.36% training accuracy and 98.72% validation accuracy. The proposed model utilizes data processing in all aspects, i.e. image denoising to reduce the data redundancy, training by ensemble learning to provide higher results than that of single models. The final classification by a fuzzy ARTMAP model that controls the number of nodes depending upon the performance makes robust accurate classification.

Research limitations/implications

Research in the field of medical applications is an ongoing method. More advanced algorithms are being developed for better classification. Still, the scope is there to design the models in terms of better performance, practicability and cost efficiency in the future. Also, the ensemble models may be chosen with different combinations and characteristics. Only signal instead of images may be verified for this proposed model. Experimental analysis shows the improved performance of the proposed model. This method needs to be verified using practical models. Also, the practical implementation will be carried out for its real-time performance and cost efficiency.

Originality/value

The proposed model is utilized for denoising and to reduce the data redundancy so that the feature selection is done using KPCA. Training and classification are performed using heterogeneous ensemble model designed using RNN, LSTM and GRU as base classifiers to provide higher results than that of single models. Use of adaptive fuzzy mapping model makes the final classification accurate. The effectiveness of combining these methods to a single model is analyzed in this work.
Modified vector field and nonlinear guidance law for low-cost UAV path following
Authors: He Mo , Wang Xiaogang , Cui Naigang
Published: June 2022

Purpose

The purpose of this paper is to present a high accuracy path following method for low-cost fixed-wing UAVs.

Design/methodology/approach

The original vector field (VF) algorithm is condensed. A spatial integration mechanism is added to the existing VF and nonlinear guidance law, aiming to decrease steady-state cross-track-error and cope with long-term disturbance.

Findings

Numerical simulations show the proposed method could diminish steady-state cross-track-error effectively. Test flights show the proposed method is applicable on low-cost fixed-wing UAVs.

Practical implications

The path following accuracy shown in simulations and test flights indicates the proposed method could be deployed in scenarios including inflight rendezvous, formation, trafficway take-off and landing.

Originality/value

This paper provides an improved high-accuracy path following method for low-cost fixed-wing UAVs.
Developing a monitoring and evaluation framework in a humanitarian non-profit organisation using agile methodology
Authors: Kelly Leanne M. , Goodall Julia , Lombardi Lauren
Published: June 2022

Purpose

This paper relays the process the authors used to develop a monitoring and evaluation (M&E) framework in the emergency services team at Australian Red Cross. The paper aims to provide useful information and guidance to support others to build and improve their M&E frameworks, which are fundamental for guiding achievement of department or organisational goals.

Design/methodology/approach

This paper uses a case study to describe the participatory agile methodology applied to develop the framework. The completed framework includes indicators mined from pre-existing literature and highlights the benefits of using an agile and participatory approach to cultivate user buy-in, enhance operational relevance and create timely results.

Findings

Development of the M&E framework streamlined measurement across the team, improved programmatic strategic alignment, identified gaps in data collection and promoted utilisation of evaluative information. Additionally, it was an exercise in evaluation capacity building, with many process uses, which positively influenced the implementation stage.

Originality/value

There are very few scholarly papers that outline the process taken to develop M&E frameworks, and none in the humanitarian, emergency services field. Additionally, this paper offers an innovative use of agile in facilitating a collaborative, sustainable and meaningful framework.
Applying situational analysis to examine the impact of VOICES on people experiencing multiple disadvantage
Authors: Spyropoulos Konstantinos , Gidlow Christopher James , McCormack Fiona , Meakin Andy , Hine Rachele , Fedorowicz Sophia
Published: June 2022

Purpose

This paper reports the use of situational analysis as a systems methodology to evaluate the voices of independence change and empowerment in the Stoke-on-Trent (VOICES) partnership project.

Design/methodology/approach

Using situational analysis and drawing on a range of secondary data sources, a three-stage conceptual mapping process provided a detailed picture of both the non-linear interlinkage and complexity of the local system that VOICES was working to influence, as well as the processes that shaped the experiences of those who act within the situation.

Findings

Data highlighted the systemic challenges facing VOICES customers (e.g. stigma and marginalisation and lack of legal literacy), progress made by VOICES in each of their priority areas and an overarching theme of VOICES promoting equity (rather than equality) to address failure demand in the system of support for people with multiple needs and disadvantage.

Originality/value

The authors present the novel application of situational analysis to demonstrate a substantial impact of VOICES while demonstrating the value of this methodology for complex systems thinking research and evaluation.
The synergistic impact of market and technology orientations on sustainable innovation performance: evidence from manufacturing firms
Authors: Alerasoul S. Alireza , Afeltra Giovanna , Bouncken Ricarda B. , Hakala Henri
Published: June 2022

Purpose

The purpose of this study is to identify groups of manufacturing firms having different combinations of strategic orientation (market and technology orientations) and compare the viable groups for differences in their sustainable innovation (SI) performance.

Design/methodology/approach

A sample of 373 Italian manufacturing firms is clustered (using non-hierarchical cluster analysis) based on their combinations of market orientation (MO) and technology orientation (TO). Subsequently, the one-way between-groups analysis of variance (ANOVA) with post-hoc tests is conducted to detect how the resulting groups differ in their SI performance.

Findings

The synergistic co-alignment of TO with both dimensions of MO (i.e. responsive and proactive) can help firms enhance their performance regarding SI. Amongst the groups of manufacturing firms identified in the context of this research, ‘future-oriented entrepreneurs’ appear to represent the strongest combination of MO with TO, leading them to achieve higher levels of SI performance.

Research limitations/implications

This study, by referring to a survey-based empirical study of manufacturing firms in Italy, extends the literature by arguing that higher levels of balanced TO–MO results in greater SI performance. To confirm and extend the results of this work, future research should assess the examined combinations of orientations in other contexts, and with respect to other performance variables (e.g. sustainable entrepreneurship).

Practical implications

By recognizing the real value of foresight practices, manufacturing firms should be equipped with organizational capabilities that enable them to systematically predict potential discontinuities, explore the future and simultaneously maximize their innovation and technology capacity. The findings of this research provide insights to managers on how to invest in resources linked to different configurations of MO and TO so that they can lead to the improvement of sustainability-oriented innovation performance.

Originality/value

This work represents a first attempt to explore the viable combinations of MO (including responsive and proactive dimensions) with TO in the manufacturing context, and to investigate how these combinations contribute to different levels of SI performance.
The influence of corporate governance on the performance of family-controlled firms: exploring the effects of legal jurisdiction
Authors: Xu Ella Guangxin , Yang Joey W. , Shan Yuan George , Graves Chris
Published: June 2022

Purpose

This study investigates effects of corporate governance on the financial performance of family-controlled firms and how these effects differ between common law and civil law jurisdictions.

Design/methodology/approach

This study applies a number of corporate governance measures to the largest 243 publicly listed family-controlled businesses worldwide from 2009 to 2018. The corporate governance measures include board independence, board gender diversity, corporate governance index (CGI) and the percentage of family ownership.

Findings

The empirical evidence indicates that board independence improves financial performance; this positive effect is more pronounced in common law than civil law jurisdictions. Board gender diversity has a negative impact on financial performance under common law but a positive impact in civil law jurisdictions. Moreover, the CGI and family ownership structure are positively associated with financial performance, and no difference is found between the two jurisdiction types. In addition, family ownership negatively moderates CGI in civil law countries only.

Originality/value

This study provides new insight on the relevance of considering jurisdictional differences when examining the effect of corporate governance on performance. The study also addresses important concerns in family business research relating to unobserved heterogeneity and endogeneity. Implications of these for research and practice are discussed in the paper.
Organisational capabilities and small and medium sized firms’ attainment of innovation outcomes: the moderating roles of exports and formal business networks
Authors: Liu Gordon , Liu Weixi , Ko Wai Wai
Published: June 2022

Purpose

The authors examine the influence of planning and execution capability (PEC) and operational improvement capability (OIC) on small-and-medium-sized firms’ (SMEs) attainment of different innovation outcomes under the conditions of exports and formal business networks, based on the capability-based perspective and organisational learning literature.

Design/methodology/approach

The authors analyse time-series data about UK SMEs, extracted from the 2015 and 2016 UK Longitudinal Small Business Surveys (LSBS).

Findings

The authors failed to find any direct effects of PEC and OIC on product innovation outcomes. However, the authors discovered that OIC supports the generation of process innovation outputs more strongly than PEC. Additionally, exports and formal business networks provide SMEs with different learning opportunities. The authors find limited support that exports amplify the beneficial effect of PEC on product innovation outcomes more than formal business networks. On the other hand, formal business networks strengthen the effect of PEC on process innovation outcomes more than exports. As a result, exports reduce the beneficial effect of OIC on product innovation outcomes more than formal business networks. However, formal business networks weaken the beneficial effect of OIC more than exports.

Originality/value

The authors distinguish between two types of organisational capabilities – PEC and OIC – and examine their impact on SMEs in achieving innovation outcomes. The authors also identify SMEs’ involvement in exports and formal business networks as the important boundary conditions for such effects. xD; xA; xD; xA;