bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrostatically regulated active site assembly governs reactivity in non-heme iron halogenases
Authors: Smithwick Elizabeth R. , Wilson R. Hunter , Chatterjee Sourav , Pu Yu , Dalluge Joseph J. , Damodaran Anoop Rama , Bhagi-Damodaran Ambika
Published: May 2023

Non-heme iron halogenases (NHFe-Hals) catalyze the direct insertion of a chloride/bromide ion at an unactivated carbon position using a high-valent haloferryl intermediate. Despite more than a decade of structural and mechanistic characterization, how NHFe-Hals preferentially bind specific anions and substrates for C-H functionalization remains unknown. Herein, using lysine halogenating BesD and HalB enzymes as model systems, we demonstrate strong positive cooperativity between anion and substrate binding to the catalytic pocket. Detailed computational investigations indicate that a negatively charged glutamate hydrogen-bonded to iron’s equatorial-aqua ligand acts as an electrostatic lock preventing both lysine and anion binding in the absence of the other. Using a combination of UV-Vis spectroscopy, binding affinity studies, stopped-flow kinetics investigations, and biochemical assays, we explore the implication of such active site assembly towards chlorination, bromination, and azidation reactivities. Overall, our work highlights previously unknown features regarding how anion-substrate pair binding govern reactivity of iron halogenases that are crucial for engineering next-generation C-H functionalization biocatalysts.
In vitroreconstitution of SARS CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g
Authors: Abaeva Irina S. , Arhab Yani , Miścicka Anna , Hellen Christopher U. T. , Pestova Tatyana V.
Published: May 2023

SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted itin vitroon β-globin, EMCV IRES and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required Nsp1 and only canonical translational components (40S subunits and initiation factors), arguing against involvement of a putative cellular RNA endonuclease. Requirements for initiation factors differed for these mRNAs, reflecting their requirements for ribosomal attachment. Cleavage of CrPV IRES mRNA was supported by a minimal set of components consisting of 40S subunits and eIF3g’s RRM domain. The cleavage site was located in the coding region 18 nucleotides downstream from the mRNA entrance indicating that cleavage occurs on the solvent side of the 40S subunit. Mutational analysis identified a positively charged surface on Nsp1’s N-terminal domain (NTD) and a surface above the mRNA-binding channel on eIF3g’s RRM domain that contain residues essential for cleavage. These residues were required for cleavage on all three mRNAs, highlighting general roles of Nsp1-NTD and eIF3g’s RRM domain in cleavageper se, irrespective of the mode of ribosomal attachment.
m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis
Authors: Xiao Ling , De Jesus Dario F. , Ju Cheng-Wei , Wei Jiang-Bo , Hu Jiang , DiStefano-Forti Ava , Tsuji Tadataka , Cero Cheryl , Männistö Ville , Manninen Suvi M. , Wei Siying , Ijaduola Oluwaseun , Blüher Matthias , Cypess Aaron M. , Pihlajamäki Jussi , Tseng Yu-Hua , He Chuan , Kulkarni Rohit N.
Published: May 2023

Brown adipose tissue (BAT) has the capacity to regulate systemic metabolism through the secretion of signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. In this study, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14), modifies the BAT secretome to initiate inter-organ communication to improve systemic insulin sensitivity. Importantly, these phenotypes are independent of UCP1-mediated energy expenditure and thermogenesis. Using lipidomics, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KO-BAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a levels are inversely correlated with insulin sensitivity in humans. Furthermore,in vivoadministration of PGE2 and PGF2a in high-fat diet-induced insulin-resistant obese mice recapitulates the phenotypes of METTL14 deficient animals. PGE2 or PGF2a improves insulin signaling by suppressing the expression of specific AKT phosphatases. Mechanistically, METTL14-mediated m6A installation promotes decay of transcripts encoding prostaglandin synthases and their regulators in human and mouse brown adipocytes in a YTHDF2/3-dependent manner. Taken together, these findings reveal a novel biological mechanism through which m6A-dependent regulation of BAT secretome regulates systemic insulin sensitivity in mice and humans.

Highlights

Mettl14KO-BAT improves systemic insulin sensitivity via inter-organ communication;

PGE2 and PGF2a are BAT-secreted insulin sensitizers and browning inducers;

PGE2 and PGF2a sensitize insulin responses through PGE2-EP-pAKT and PGF2a-FP-AKT axis;

METTL14-mediated m6A installation selectively destabilizes prostaglandin synthases and their regulator transcripts;

Targeting METTL14 in BAT has therapeutic potential to enhance systemic insulin sensitivity

Abstract Figure
Evolution of the spider homeobox gene repertoire by tandem and whole genome duplication
Authors: Aase-Remedios Madeleine E. , Janssen Ralf , Leite Daniel J. , Sumner-Rooney Lauren , McGregor Alistair P.
Published: May 2023

Gene duplication generates new genetic material that can contribute to the evolution of gene regulatory networks and phenotypes. Duplicated genes can undergo subfunctionalisation to partition ancestral functions and/or neofunctionalisation to assume a new function. We previously found there had been a whole genome duplication (WGD) in an ancestor of arachnopulmonates, the lineage including spiders and scorpions but excluding other arachnids like mites, ticks, and harvestmen. This WGD was evidenced by many duplicated homeobox genes, including two Hox clusters, in spiders. However, it was unclear which homeobox paralogues originated by WGD versus smaller-scale events such as tandem duplications. Understanding this is key to determining the contribution of the WGD to arachnopulmonate genome evolution. Here we characterised the distribution of duplicated homeobox genes across eight chromosome-level spider genomes. We found that most duplicated homeobox genes in spiders are consistent with an origin by WGD. We also found two copies of conserved homeobox gene clusters, including the Hox, NK, HRO,Irx, and SINE clusters, in all eight species. Consistently, we observed one copy of each cluster was degenerated in terms of gene content and organisation while the other remained more intact. Focussing on the NK cluster, we found evidence for regulatory subfunctionalisation between the duplicated NK genes in the spiderParasteatoda tepidariorumcompared to their single-copy orthologues in the harvestmanPhalangium opilio. Our study provides new insights into the relative contributions of multiple modes of duplication to the homeobox gene repertoire during the evolution of spiders and the function of NK genes.
Mitochondrial calcium signaling mediated transcriptional regulation of keratin filaments is a critical determinant of melanogenesis
Authors: Tanwar Jyoti , Ahuja Kriti , Sharma Akshay , Sehgal Paras , Ranjan Gyan , Sultan Farina , Priya Anshu , Venkatesan Manigandan , Yenamandra Vamsi K , Singh Archana , Madesh Muniswamy , Sivasubbu Sridhar , Motiani Rajender K
Published: May 2023

Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca2+signaling. However, role of mitochondrial Ca2+signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+uptake.In vitrogain and loss of function studies demonstrated that Mitochondrial Ca2+Uniporter (MCU) is crucial for melanogenesis while the MCU rheostats, MCUb and MICU1 negatively control melanogenesis. Zebrafish and mouse models showed that MCU plays a vital role in pigmentationin vivo. Mechanistically, MCU controls activation of transcription factor NFAT2 to induce expression of three keratins (keratin 5, 7 and 8), which we report as positive regulators of melanogenesis. Interestingly, keratin 5 in turn modulates mitochondrial Ca2+uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca2+signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca2+signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions.

Highlights

MCU complex mediated mitochondrial Ca2+uptake is a novel regulator of vertebrate pigmentation

Keratin filaments bridge mitochondrial Ca2+signaling to melanosome biogenesis and maturation

Transcription factor NFAT2 connects mitochondrial Ca2+dynamics to keratins expression

MCU-NFAT2-Keratin 5 signaling module generates a negative feedback loop to maintain mitochondrial Ca2+homeostasis and to ensure optimal melanogenesis

Inhibiting MCU with mitoxantrone, an FDA approved drug, leads to reduction in physiological pigmentation
Visualizing dynamic competence pili and DNA capture throughout the long axis ofBacillus subtilis
Authors: Zuke Jason D. , Erickson Rachel , Hummels Katherine R. , Burton Briana M.
Published: May 2023

The first step in the process of bacterial natural transformation is DNA capture. Although long-hypothesized based on genetics and functional experiments, the pilus structure responsible for initial DNA-binding had not yet been visualized forBacillus subtilis. Here, we visualize functional competence pili inBacillus subtilisusing fluorophore-conjugated maleimide labeling in conjunction with epifluorescence microscopy. In strains that produce pilin monomers within ten-fold of wild type levels, the median length of detectable pili is 300nm. These pili are retractile and associate with DNA. Analysis of pilus distribution at the cell surface reveals that they are predominantly located along the long axis of the cell. The distribution is consistent with localization of proteins associated with subsequent transformation steps, DNA-binding and DNA translocation in the cytosol. These data suggest a distributed model forB. subtilistransformation machinery, in which initial steps of DNA capture occur throughout the long axis of the cell and subsequent steps may also occur away from the cell poles.

Importance

This work provides novel visual evidence for DNA translocation across the cell wall duringBacillus subtilisnatural competence, an essential step in the natural transformation process. Our data demonstrate the existence of natural competence associated, retractile pili that can bind exogenous DNA. Furthermore, we show that pilus biogenesis occurs throughout the cell long axis. These data strongly support DNA translocation occurring all along the lateral cell wall during natural competence, wherein pili are produced, bind to free DNA in the extracellular space, and finally retract to pull the bound DNA through the gap in the cell wall created during pilus biogenesis.
The Tgf-β family member Gdf6Y determines the male sex inNothobranchius furzeriby suppressing oogenesis-inducing genes
Authors: Richter Annekatrin , Mörl Hanna , Thielemann Maria , Kleemann Markus , Geißen Raphael , Schwarz Robert , Albertz Carolin , Koch Philipp , Petzold Andreas , Groth Marco , Hartmann Nils , Herpin Amaury , Englert Christoph
Published: May 2023

The short-lived African killifishNothobranchius furzerilives in seasonal freshwater ponds and has evolved remarkable traits to survive in this limited environment. One of those traits is a genetic XX/XY sex-determination system, which ensures an equal distribution of both sexes. Comparisons of female and male genomic sequences identified the Y-chromosomal copy of the TGF-β family membergdf6as the candidate male sex-determining (SD) gene, which was namedgdf6Yin contrast to the X-chromosomal allelegdf6X. CRISPR/Cas9-mediated inactivation ofgdf6YinN. furzeriled to a complete male-to-female sex reversal in XY animals. The homozygous inactivation ofgdf6Xon the other hand led to a detrimental phenotype post-hatching. This phenotype was compensated bygdf6Y, revealing that the latter became the SD gene while retaining at least some of its originalgdf6function.Gdf6Yis expressed in testicular somatic cells already prior to hatching, where it represses the germ cell-intrinsic feminizing genefoxl2l. We have identified components of the TGF-β signaling pathway, especially the inhibitor of DNA binding genesid1/2/3, and the mRNA decay activatorzfp36l2, as Gdf6Y targets. We conclude that Gdf6Y exerts its function as the male sex-determining gene by suppressing female-specific genes in the developing gonad of maleN. furzeri.
Acute ampakines increase voiding function and coordination in a rat model of SCI
Authors: Rana Sabhya , Alom Firoj , Martinez Robert C , Fuller David D , Mickle Aaron D
Published: May 2023

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The “low impact” ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.
Rapid decline of prenatal maternal effects with age is independent of postnatal environment in a precocial bird
Authors: Vedder Oscar , Tschirren Barbara , Postma Erik , Moiron Maria
Published: May 2023

Maternal effects are an important source of phenotypic variation with potentially large fitness consequences, but how their importance varies with the quality of the environment across an individual’s ontogeny is poorly understood. We bred Japanese quail (Coturnix japonica) of known pedigree and experimentally manipulated the quality of offspring diet, to estimate the importance of prenatal maternal effects in shaping variation in body mass from hatching to adulthood. Maternal genetic effects on body mass at hatching were strong, and largely caused by variation in egg mass, but their importance rapidly declined with age. Whereas there was a large effect of diet on growth, this did not affect the decline of maternal effects variance. The importance of additive genetic and residual variance increased with age, with the latter being considerably larger in the poor diet treatment. Hence, we found no evidence for prenatal maternal effect by postnatal environment interactions, and that prenatal maternal effects are rapidly replaced by direct additive genetic and residual effects when offspring start to develop outside the egg. Thereby these results shed new light on the dynamics of the role of maternal versus offspring genes across ontogeny and environments.
Modifications to the SR-Rich Region of the SARS-CoV-2 Nucleocapsid Regulate Self-Association and Attenuate RNA Interactions
Authors: Reardon Patrick N. , Stuwe Hannah , Shah Sahana , Yu Zhen , Hughes Kaitlyn , Barbar Elisar J.
Published: May 2023

The nucleocapsid protein (N) of SARS-CoV-2 is essential for virus replication, genome packaging, and maturation. N is comprised of two folded domains that are separated by a highly conserved, disordered, Ser/Arg-rich linker, and flanked by disordered tails. Using NMR spectroscopy and analytical ultracentrifugation we identify an alpha-helical region in the linker that undergoes concentration dependent self-association. NMR and gel shift assays show that the linker binds viral RNA but this binding is dampened by both phosphorylation and a naturally occurring mutation, whereas in contrast, RNA binding to the full-length protein is not affected. Interestingly, phase separation with RNA is significantly reduced upon phosphorylation but enhanced with the mutation. We attribute these differences to changes in the linker helix self-association which dissociates upon phosphorylation but forms more stable higher order oligomers in the variant. These data provide a structural mechanism for how the linker region contributes to protein-protein interactions, RNA-protein interactions, liquid-liquid phase separation and N protein regulation.
Mechanically-evoked spike responses of pentascolopidial chordotonal organs ofDrosophilalarvae
Authors: Warren Ben , Göpfert Martin C.
Published: May 2023

Stretch-sensitive ensembles of neurons in insects, known as Chordotonal organs (COs), function in proprioception, the detection of sound and substrate vibrations. Here we characterize the mechanical sensitivity of the lateral pentascolopidial CO (lch5) ofDrosophilalarvae to establish its postulated role in proprioception. We developed a physiologically realistic method to replicate proprioceptive input to lch5 by pulling the apodeme (tendon) to which the tips of the neurons attach. We found that lch5 sensory neurons respond transiently with a short latency to the velocity-component of stretch displacements and the release of stretch (relaxation). The mechanosensory mutantinactive, has a decreased response to mechanical stimuli and a lower overall spontaneous spike rate. Finally, we simulated the input that lch5 receives during crawling and observed spikes coincident with the start, middle and end of each peristaltic body contraction. We provide the first characterization of proprioceptive feedback inDrosophilalarvae and firmly establish the proprioceptive function of lch5 in larval locomotion.

Summary statement

We have characterized the spiking responses of the pentascolopidial chordotonal organ of 20 Drosophila larvae to mechanical stimuli and reveal a clear role in proprioception.
Intratumoral administration of recombinant murine interleukin-12 prevents tumor progression and bone invasion
Authors: Kasahara Shun , Uchihashi Toshihiro , Inubushi Toshihiro , Kurioka Kyoko , Sugauchi Akinari , Miyagawa Kazuaki , Kogo Mikihiko , Tanaka Susumu
Published: May 2023

Background

Oral squamous cell carcinoma (OSCC) progression is accompanied by bone invasion. Therefore, maintaining oral function is necessary to regulate tumor progression. Also, interleukin-12 (IL-12), a well-known anti-tumor cytokine, can suppress osteoclast differentiation in vitro. Accordingly, this study evaluated the therapeutic effects of locally administered IL-12 in an immunocompetent mouse model with mandibular bone invasion mimicking clinical features.

Methods

We investigated anti-bone resorption effects using SCCVII subcutaneous and bone invasion models both in immunocompetent and athymic mice. Furthermore, we measured bone resorption using micro-computed tomography.

Results

Intratumoral injection of recombinant murine IL-12 (r-mIL-12) significantly prolonged immunocompetent mouse survival and suppressed tumor growth and bone resorption. Real-time PCR analysis revealed that interferon-gamma (IFN-γ) and Fas ligand (FasL) were upregulated after r-mIL-12 administration, compared to control levels. However, when the athymic mouse bone invasion model was evaluated, r-mIL-12-mediated suppression of tumor growth and bone resorption were equivalent to those observed in the control group, highlighting the key role of T cells in the bone invasion.

Conclusions

r-mIL-12 may represent a potent therapeutic agent for OSCC accompanied by bone invasion.

Intratumoral injection of recombinant murine IL-12 showed anti-tumor and anti-bone resorption effects in an immunocompetent mouse bone invasion model through a T cell-dependent mechanism.
BIG participates in the Arg/N-degron pathways and the hypoxia response inArabidopsis thaliana
Authors: Zhang Hongtao , Rundle Chelsea , Winter Nikola , Miricescu Alexandra , Mooney Brian C. , Bachmair Andreas , Graciet Emmanuelle , Theodoulou Frederica L.
Published: May 2023

BIG (also known as DOC1 and TIR3) is an 0.5 MDa protein that has been associated with multiple important functions in signalling and development through forward genetic screens inArabidopsis thaliana. However, the biochemical function(s) of BIG are unknown. Here, we investigated whether BIG plays a role in the Arg/N-degron pathways, protein regulatory mechanisms in which substrate protein fate is influenced by the N-terminal (Nt) residue. In Arabidopsis, PROTEOLYSIS1 (PRT1) is an E3 ligase with specificity for aromatic amino acids, whereas PROTEOLYSIS6 (PRT6) targets basic N-terminal residues. We crossed a big loss-of-function allele toprt6andprt1mutants and examined the stability of protein substrates. Stability of model N-degron pathway substrates was enhanced inprt6-1 big-2andprt1-1 big-2relative to the respective single mutants. Abundance of the PRT6 physiological substrates, HYPOXIA RESPONSIVE ERF (HRE)2 and VERNALIZATION (VRN)2 was similarly increased inprt6 bigdouble mutants, without increase in transcripts. Accordingly, hypoxia marker expression was enhanced inprt6 bigdouble mutants, in a manner requiring arginyltransferase activity and RAP-type ERFVII transcription factors. Transcriptomic analysis of roots not only demonstrated synergistically increased expression of a plethora of hypoxia responsive genes in the double mutant relative toprt6but also revealed other roles for PRT6 and BIG, including regulation of suberin deposition through both ERFVII-dependent and independent mechanisms, respectively. Our results show that BIG acts together with PRT6 to regulate the hypoxia response and wider processes.

Significance Statement

The N-degron pathways are a group of protein regulatory mechanisms that play important roles in plant growth, development, and response to biotic and abiotic stresses. Despite rapid progress in the last decade, key enzymatic components of the pathways remain to be identified. BIG (also known as DOC1 and TIR3) is a protein of approximately 0.5 MDa, associated with multiple, distinct roles in plants but the precise biochemical functions of this protein have remained enigmatic until now. Here we identify BIG as a new component of plant N-degron pathways that acts together with the N-recognin E3 ligase PROTEOLYSIS6 (PRT6) to control the hypoxia response and other functions inArabidopsis thaliana.
GPI-anchored Gas1 protein regulates cytosolic proteostasis in yeast
Authors: Wang Yuhao , Ruan Linhao , Li Rong
Published: May 2023

Decline in protein homeostasis (proteostasis) is a hallmark of cellular aging and aging-related diseases. Maintaining a balanced proteostasis requires a complex network of molecular machineries that govern protein synthesis, folding, localization, and degradation. Under proteotoxic stress, misfolded proteins that accumulate in cytosol can be imported into mitochondria for degradation via ‘mitochondrial as guardian in cytosol’ (MAGIC) pathway. Here we report an unexpected role of yeast Gas1, a cell wall-bound glycosylphosphatidylinositol (GPI)-anchored β-1,3-glucanosyltransferase, in differentially regulating MAGIC and ubiquitin-proteasome system (UPS). Deletion of Gas1 inhibits MAGIC but elevates polyubiquitination and UPS-mediated protein degradation. Interestingly, we found that Gas1 exhibits mitochondrial localization attributed to its C-terminal GPI anchor signal. But this mitochondria-associated GPI anchor signal is not required for mitochondrial import and degradation of misfolded proteins via MAGIC. By contrast, catalytic inactivation of Gas1 via thegas1E161Qmutation inhibits MAGIC but not its mitochondrial localization. These data suggest that the glucanosyltransferase activity of Gas1 is important for regulating cytosolic proteostasis.
SARS-CoV-2 lineage assignments using phylogenetic placement/UShER are superior to pangoLEARN machine learning method
Authors: de Bernardi Schneider Adriano , Su Michelle , Hinrichs Angie S. , Wang Jade , Amin Helly , Bell John , Wadford Debra A. , O’Toole Àine , Scher Emily , Perry Marc D. , Turakhia Yatish , De Maio Nicola , Hughes Scott , Corbett-Detig Russ
Published: May 2023

With the rapid spread and evolution of SARS-CoV-2, the ability to monitor its transmission and distinguish among viral lineages is critical for pandemic response efforts. The most commonly used software for the lineage assignment of newly isolated SARS-CoV-2 genomes is pangolin, which offers two methods of assignment, pangoLEARN and pUShER. PangoLEARN rapidly assigns lineages using a machine learning algorithm, while pUShER performs a phylogenetic placement to identify the lineage corresponding to a newly sequenced genome. In a preliminary study, we observed that pangoLEARN (decision tree model), while substantially faster than pUShER, offered less consistency across different versions of pangolin v3. Here, we expand upon this analysis to include v3 and v4 of pangolin, which moved the default algorithm for lineage assignment from pangoLEARN in v3 to pUShER in v4, and perform a thorough analysis confirming that pUShER is not only more stable across versions but also more accurate. Our findings suggest that future lineage assignment algorithms for various pathogens should consider the value of phylogenetic placement.
Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacyin vivo
Authors: Yamada Ken , Hariharan Vignesh Narayan , Caiazzi Jillian , Miller Rachael , Furguson Chantal , Sapp Ellen , Fakih Hassan , Tan Qi , Yamada Nozomi , Furgal Raymond C. , Paquette Joseph , Bramato Brianna , McHugh Nicholas , Summers Ashley , Lochmann Clemens , Godinho Bruno M.D.C. , Hildebrand Samuel , Echeverria Dimas , Hassler Matthew R. , Alterman Julia F. , DiFiglia Marian , Aronin Neil , Khvorova Anastasia
Published: May 2023

Metabolic stabilization of therapeutic oligonucleotides requires both sugar and backbone modifications, where phosphorothioate (PS) is the only backbone chemistry used in the clinic. Here, we describe the discovery, synthesis, and characterization of a novel biologically compatible backbone, extended nucleic acid (exNA). Upon exNA precursor scale up, exNA incorporation is fully compatible with common nucleic acid synthetic protocols. The novel backbone is orthogonal to PS and shows profound stabilization against 3’- and 5’-exonucleases. Using small interfering RNAs (siRNAs) as an example, we show exNA is tolerated at most nucleotide positions and profoundly improves in vivo efficacy. A combined exNA-PS backbone enhances siRNA resistance to serum 3’-exonuclease by ∼32-fold over PS backbone and >1000-fold over the natural phosphodiester backbone, thereby enhancing tissue exposure (∼6-fold), tissues accumulation (4- to 20-fold), and potency both systemically and in brain. The improved potency and durability imparted by exNA opens more tissues and indications to oligonucleotide-driven therapeutic interventions.
A Benchmark Dataset for Machine Learning in Ecotoxicology
Authors: Schür Christoph , Gasser Lilian , Perez-Cruz Fernando , Schirmer Kristin , Baity-Jesi Marco
Published: May 2023

The use of machine learning for predicting ecotoxicological outcomes is promising, but underutilized. The curation of data with informative features requires both expertise in machine learning as well as a strong biological and ecotoxicological background, which we consider a barrier of entry for this kind of research. Additionally, model performances can only be compared across studies when the same dataset, cleaning, and splittings were used. Therefore, we provideADORE, an extensive and well-described dataset on acute aquatic toxicity in three relevant taxonomic groups (fish, crustaceans, and algae). The core dataset describes ecotoxicological experiments and is expanded with phylogenetic and species-specific data on the species as well as chemical properties and molecular representations. Apart from challenging other researchers to try and achieve the best model performances across the whole dataset, we propose specific relevant challenges on subsets of the data and include datasets and splittings corresponding to each of these challenge as well as in-depth characterization and discussion of train-test splitting approaches.
Nitrogen source and Nod factor signaling map out the assemblies ofLotus japonicusroot bacterial communities
Authors: Tao Ke , Jensen Ib T. , Zhang Sha , Villa-Rodríguez Eber , Blahovska Zuzana , Salomonsen Camilla Lind , Martyn Anna , Björgvinsdóttir Þuríður Nótt , Kelly Simon , Janss Luc , Glasius Marianne , Waagepetersen Rasmus , Radutoiu Simona
Published: May 2023

Symbiosis with soil-dwelling bacteria that fix atmospheric nitrogen allows legume plants to grow in nitrogen-depleted soil. Symbiosis impacts the assembly of root microbiota, but it is not known how this process takes place and whether it is independent of nitrogen nutrition. We use plant and bacterial mutants to address the role of Nod factor signaling onLotus japonicusroot microbiota assembly. We found that Nod factors are produced by symbionts to activate Nod factor signaling in the host, and this modulates the assembly of a symbiotic root microbiota.Lotusplants grown in symbiosis-permissive or suppressive soils delineated three nitrogen-dependent nutritional states: starved, symbiotic, or inorganic. We found that root and rhizosphere microbiomes associated with these states differ in composition and connectivity, demonstrating that symbiosis and inorganic nitrogen impact the legume root microbiota differently. Finally, we demonstrated that selected bacterial genera delineating state-dependent microbiomes have a high level of accurate prediction.
A configural context signal simultaneously but separably drives positioning and orientation of hippocampal place fields
Authors: Cheng Han Yin , Overington Dorothy W , Jeffery Kate J.
Published: May 2023

Effective self-localization requires that the brain can resolve ambiguities in incoming sensory information arising from self-similarities (symmetries) in the environment structure. We investigated how place cells use environmental cues to resolve the ambiguity of a rotationally symmetric environment, by recording from hippocampal CA1 in rats exploring a ‘2-box’. This apparatus comprises two adjacent rectangular compartments, identical but with directionally opposed layouts (cue card at one end and central connecting doorway) and distinguished by their odor contexts (lemon vs. vanilla). Despite the structural and visual rotational symmetry of the boxes, no place cells rotated their place fields. The majority remapped their fields between boxes but some repeated them, maintaining a translational symmetry and thus adopting a relationship to the layout that was conditional on the odor. In general, the place field ensemble maintained a stable relationship to environment orientation as defined by the odors, but sometimes the whole ensemble rotated its firingen bloc, decoupling from the odor context cues. While the individual elements of these observations – odor remapping, place field repetition, ensemble rotation and decoupling from context – have been reported in isolation, the combination in the one experiment is incompletely explained within current models. We redress this by proposing a model in which odor cues enter into a three-way association with layout cues and head direction, creating a configural context signal that facilitates two separate processes: place field orientation, and place field positioning. This configuration can subsequently still function in the absence of one of its components, explaining the ensemble decoupling from odor. We speculate that these interactions occur in retrosplenial cortex, because it has previously been implicated in context processing, and all the relevant signals converge here.
Measuring the interdisciplinary characteristics of Chinese research in library and information science based on knowledge elements
Authors: Zeng Jinxiang , Cao Shujin , Chen Yijin , Pan Pei , Cai Yafang
Published: May 2023

Purpose

This study analyzed the interdisciplinary characteristics of Chinese research studies in library and information science (LIS) measured by knowledge elements extracted through the Lexicon-LSTM model.

Design/methodology/approach

Eight research themes were selected for experiment, with a large-scale (N = 11,625) dataset of research papers from the China National Knowledge Infrastructure (CNKI) database constructed. And it is complemented with multiple corpora. Knowledge elements were extracted through a Lexicon-LSTM model. A subject knowledge graph is constructed to support the searching and classification of knowledge elements. An interdisciplinary-weighted average citation index space was constructed for measuring the interdisciplinary characteristics and contributions based on knowledge elements.

Findings

The empirical research shows that the Lexicon-LSTM model has superiority in the accuracy of extracting knowledge elements. In the field of LIS, the interdisciplinary diversity indicator showed an upward trend from 2011 to 2021, while the disciplinary balance and difference indicators showed a downward trend. The knowledge elements of theory and methodology could be used to detect and measure the interdisciplinary characteristics and contributions.

Originality/value

The extraction of knowledge elements facilitates the discovery of semantic information embedded in academic papers. The knowledge elements were proved feasible for measuring the interdisciplinary characteristics and exploring the changes in the time sequence, which helps for overview the state of the arts and future development trend of the interdisciplinary of research theme in LIS.
Configural paths for IoTs and big data analytics acceptance for healthcare improvement: a fuzzy-set qualitative comparative analysis
Authors: Edu Abeeku Sam
Published: May 2023

Purpose

This study investigates the pathways for adopting IoTs and BDA technologies to improve healthcare management.

Design/methodology/approach

The study relied on 445 healthcare professionals' perspectives to explore different causal pathways to IoTs and BDA adoption and usage for daily healthcare management. The Fussy-set Qualitative Comparative Analysis was adopted to explore the underlying pathways for healthcare management.

Findings

The empirical analysis revealed six different configural paths influencing the acceptance and use of IoTs and BDA for healthcare improvement. Two key user topologies from the six configural paths, digital literacy and ease of use and social influence and behavioural intentions, mostly affect the paths for using digital health technologies by healthcare physicians.

Research limitations/implications

Despite this study's novel contributions, limitations include the fsQCA methodology, perceptual data and the context of the study. The fsQCA methodology is still evolving with different interpretations, although it reveals new insights and as such further studies are required to explain the configural paths of social phenomena. Additionally, future research should consider other constructs beyond the UTAUT and digital literacy to illustrate configural paths to healthcare technology acceptance and usage. Again, the views of healthcare professionals are perceptual data. Hence future research on operational data will support significant contributions towards pathways to accept and use emerging technologies for healthcare improvement. Lastly, this study is from a developing country perspective where emerging digital healthcare technology is still emerging to support healthcare management. Hence, more investigation from other cross-country analyses of configural paths for digital technology deployment in healthcare will enhance the conversation with IoTs and BDA for healthcare management.

Practical implications

Holistically, the acceptance and use of healthcare technologies and platforms is not solely on their capabilities, but a combination of distinct factors driven by users' perspectives. This offers healthcare administrators and institutions to essentially reflect on the distinct combinations of conditions favourable to health professionals who can use IoTs and BDA for healthcare improvement.

Originality/value

This study is among the few scholarly works to empirically investigate the configural paths to support healthcare improvement with emerging technologies. Using fsQCA is a unique contribution to existing information system literature for configural paths for healthcare improvement with emerging digital technologies.
Exploring the application of BIM in Tanzanian public sector projects using social network analysis
Authors: Abdallah Abdullatif , Doloi Hemanta , Holzer Dominik
Published: May 2023

Purpose

The present study employs social network analysis (SNA) to demonstrate the extent to which various building information modeling (BIM) functions can be used to address significant issues faced by the Tanzanian public sector construction projects.

Design/methodology/approach

This study adopted secondary data obtained from a comprehensive literature review on core BIM functions and the underlying issues faced by the Tanzanian public sector construction projects. This study then adopted SNA for associating the BIM functions with relevant construction issues.

Findings

For Objective 1, the findings revealed that BIM can address 68% of significant issues faced by the Tanzanian public sector construction projects. For Objective 2, the findings revealed that the identified functions mainly addressed issues in the early phases of the project. Finally, for Objective 3, the most effective function was “spatial coordination.”

Research limitations/implications

This literature-based study does not fully capture both the current contextual issues faced by the industry and the BIM capability of stakeholders involved. In addition, this research does not distinguish between public project size and type which can influence the types of issues faced and consequently the use of BIM function. Accordingly, the research presented in this study needs to be complemented by on-the-ground feedback of industry stakeholders and needs to investigate how project size and type impacts the types of issues that emerge and the use of BIM.

Practical implications

With respect to practice, the findings of the present study highlight key BIM functions practitioners can begin to target.

Social implications

In Tanzania, public sector construction projects contribute greatly to social development of Tanzania's population. Owing to the current state of public sector projects underperforming and the negative impact the projects have on the country's development, an intervention measure such as BIM has the potential to enhance the effective and efficient delivery of these projects and thereby promote the social development of the country's population.

Originality/value

With respect to theory, this study demonstrates how core functions of BIM can be mapped with various construction-related issues in order to evaluate the efficacies of the BIM-based investments for improving overall performance in the public sector projects. With respect to practice, the method illustrated in the present study can be applied by policymakers and practitioners to identify core BIM functions to target to address pressing contextual issues faced by public sector projects in the respective contexts.
Managing interorganizational renqing practices in high-performance organizations in Taiwan: the when, where and how of renqing giving
Authors: Hui Wei-Shen , Chen Houn-Gee , Chiu Yi-Te , Raskovic Matevz (Matt)
Published: May 2023

Purpose

Relationships are a critical success factor for business operations across markets with dominant Chinese culture, like Taiwan. The intersection of a high-quality institutional environment and a traditional Chinese cultural background in Taiwan provides a unique setting for exploring different types of relational mechanisms and ensuing renqing practices (i.e. reciprocal exchange of favors with empathy). The purpose of this paper is to examine when, where and how Taiwanese high-performance organizations manage and deploy interorganizational renqing across their business relationship portfolios. Answering these questions can help build a theory of interorganizational renqing and advance interorganizational reciprocity theorization more generally.

Design/methodology/approach

This research is motivated by two key research questions. First is related to how renqing givers understand renqing in the context of their organizations and their interorganizational business relationship portfolios. Second, whether organizations prefer a neutral renqing balance, a renqing debt or a renqing surplus is another point of interest. The study is based on interviews with upper echelon elite informants at six high-performing Taiwanese organizations with business relationship portfolios worldwide.

Findings

It is found that interorganizational renqing is deployed as a hybrid resource, taking on the functions of both an investment and a type of insurance against risk. Two notable differences between interorganizational and interpersonal renqing are also noted. First, the social exchange norm aspect of renqing points to salient social exchange norms also in interorganizational exchanges. This confirms the importance of understanding not only the regulative and normative dimensions of business relationships, as a type of institution, but also the cognitive dimensions and underlying institutional logics. Second, this study shows that unlike at the interpersonal level, the notion of renqing debt is not common at the interorganizational level – at least not within high-performance organizations with market leader positions.

Originality/value

This study explores interorganizational renqing practices and their strategic deployment through the use of “accessing” and “embedding” relational mechanisms. The study also adds to the poorly understood nature of interorganizational reciprocity and provides support for developing a theory of interorganizational renqing, as a form of interorganizational reciprocity within a Chinese cultural context.
The source of MNE superiority from within or from outside? – A response to “the importance of being transnational”
Authors: Forsgren Mats , Yamin Mo
Published: May 2023

Purpose

The purpose of this paper is to respond to the comments by professor Ietto-Gillies on the paper on “The MNE as the Crown of Creation?”

Design/methodology/approach

The authors argue that the key points made in the commentary are broadly complementary to the arguments set out in the “Crown of Creation?”

Findings

The authors agree with the commentary that sources of advantages of multinationality lie “outside the MNE” – through its interactions with national governments and organised labour. However, the authors would caution that the achievement of such advantages may encounter constraints.

Research limitations/implications

The original paper (“The MNE as the Crown of Creation?”) was a critique of mainstream theories of the MNE regarding the assumed superiority of the MNE. The response to the paper makes the argument that any superiority associated with MNE must be sought in its interactions with other actors.

Practical implications

The argument suggests that MNE managers seeking to exploit the advantage of multinationality through production shifting must be aware of the system-wide consequences of such actions.

Social implications

Given the conceptual nature of the argument and the level of abstraction, solid social implications can only be drawn tentatively.

Originality/value

The key novelty in the response paper is the possible negative effect – for MNEs – of unconstrained exercise of production shifting.
Performance reporting in the healthcare sector: evidence from Italian healthcare organisations
Authors: Aversano Natalia , Ferullo Diana , Nicolò Giuseppe , Ardito Nadia
Published: May 2023

Purpose

The present research aims to understand the performance disclosure levels provided by Italian healthcare organisations (HCOs). The authors conducted this study to assess the transparency of HCOs' performance reporting processes by examining the amount and the type of information disclosed in Annual Performance Reports (APRs).

Design/methodology/approach

The present study uses a qualitative research methodology based on manual content analysis. The APRs of a sample of 171 Italian public HCOs were analysed.

Findings

Results evidence that the APRs provide a sufficient level of disclosure of performance information, putting high attention on the epidemiological conditions; however, the APRs do not present a strong information function for stakeholders' decision-making purposes. The Italian HCOs APRs are not easily understandable because the APRs are not very concise and present information mainly in discursive terms with limited graphic support.

Originality/value

To the best of the authors' knowledge, this is the first research investigating both the extent and type of performance information reported by Italian HCOs in the APRs, considering the particular contextual conditions caused by the most significant challenge the healthcare (HC) sector has faced in recent years: the epidemiological crisis of the coronavirus disease 2019 (COVID-19). The study also explores whether APRs are currently used by HCOs as a merely regulatory requirement or as an information tool for accountability and decision-making purposes.