bluuebunny/crossref_metadata_2025 huggingface dataset:
The phycobilisome linker protein ApcG interacts with photosystem II and regulates energy transfer to photosystem I inSynechocystis sp.PCC 6803
Authors: Espinoza-Corral Roberto , Iwai Masakazu , Zavřel Tomáš , Lechno-Yossef Sigal , Sutter Markus , Červený Jan , Niyogi Krishna K. , Kerfeld Cheryl A.
Published: May 2023

Photosynthetic organisms harvest light using pigment-protein super-complexes. In cyanobacteria, these are water-soluble antennae known as phycobilisomes (PBSs). The light absorbed by PBS is transferred to the photosystems in the thylakoid membrane to drive photosynthesis. The energy transfer between these super-complexes implies that protein-protein interactions allow the association of PBS with the photosystems. However, the specific proteins involved in the interaction of PBS with the photosystems are not fully characterized. Here, we show that the newly discovered PBS linker protein ApcG interacts specifically with photosystem II through its N-terminal region. Growth of cyanobacteria is impaired inapcGdeletion strains under light-limiting conditions. Furthermore, complementation of these strains using a phospho-mimicking version of ApcG exhibit reduced growth under normal growth conditions. Interestingly, the interaction of ApcG with photosystem II is affected when a phospho-mimicking version of ApcG is used, targeting the positively charged residues interacting with thylakoid membrane suggesting a regulatory role mediated by phosphorylation of ApcG. Low temperature fluorescence measurements showed increased photosystem I fluorescence inapcGdeletion and complementation strains. The photosystem I fluorescence was the highest in the phospho-mimicking complementation strain while pull-down experiment showed no interaction of ApcG with PSI under any tested condition. Our results highlight the importance of ApcG for selectively directing energy harvested by the PBS and implies that the phosphorylation status of ApcG plays a role in regulating energy transfer from PSII to PSI.
Basal UPR activity inAspergillus fumigatusregulates adaptation to nutrient stress and is critical for the establishment of corneal infection
Authors: Kamath Manali M. , Lightfoot Jorge D. , Adams Emily M. , Wells Becca L. , Fuller Kevin K.
Published: May 2023

TheAspergillus fumigatusunfolded protein response (UPR) is a two-component relay consisting of the ER-bound IreA protein, which splices and activates the mRNA of the transcription factor HacA. SplicedhacAaccumulates under conditions of acute ER stressin vitro, and UPR null mutants are hypovirulent in a murine model of invasive pulmonary infection. In this report, we demonstrate that ahacAdeletion mutant is completely unable to establish infection in a model of fungal keratitis, a corneal infection and an important cause of ocular morbidity and unilateral blindness worldwide. Contrary to our initial prediction, however, we demonstrate thathacAsplicing is not increased above baseline conditions in the cornea, nor is the expression of genes classically associated with UPR activation, such as protein chaperones. We employed transcriptomics on wild-type andΔhacAstrains in gelatin media, as a proxy for the corneal environment, and found thathacAsupports the expression of numerous primary and secondary metabolic processes that likely promote adaptation to nutrient limitation. Taken together, our results support a model in which the cornea, similar to growth on proteinin vitro, is a source of sub-acute ER stress forA. fumigatus, but one nevertheless that requires the UPR pathway for proper adaptation. The data also suggest that this pathway could be a target for novel antifungals that improve visual outcomes for fungal keratitis patients.

AUTHOR SUMMARY

Fungal keratitis has emerged as a leading cause of ocular morbidity and unilateral blindness worldwide. Relative to other infectious contexts, however, little is known about the fungal genes or pathways that regulate invasive growth and virulence in the corneal environment. In this report, we demonstrate that genetic disruption of theAspergillus fumigatusunfolded protein response (UPR) abolishes the ability of the mold to establish infection in a mouse model of FK. Despite this critical role for virulence, however, we did not detect a concerted activation of the pathway beyond levels observed on standard medium, suggesting that the host environment is not an acute source of endoplasmic reticulum stress. Transcriptomic profiling of the wild-type and UPR-deficient strains under host-relevant nutrient conditions revealed a critical role for the pathway in regulating primary and secondary metabolism, cell wall biology, and mitochondrial function, all of which likely modulate fungal growth within and interactions with the host. These results expand our understanding of UPR regulation and function in this important mold pathogen and suggest the pathway could serve as a target for novel antifungals that improve visual outcomes in the setting of fungal keratitis.
Primary Care Post-COVID syndrome Diagnosis and Referral Coding
Authors: Willans Robert , Allsopp Gail , Jonsson Pall , Glen Fiona , Macleod John , Wei Yinghui , Greaves Felix , Bacon Sebastian , Mehrkar Amir , Walker Alex , MacKenna Brian , Fisher Louis , Goldacre Ben ,   The OpenSAFELY Collaborative,   The CONVALESCENCE Collaborative
Published: May 2023

Introduction

Guidelines for diagnosing and managing Post-COVID syndrome have been rapidly developed. Consistency of the application of these guidelines in primary care is unknown. Electronic health records provide an opportunity to review the use of codes relating to Post-COVID syndrome. This paper explores the use of primary care records as a surrogate uptake measure for NICE’s rapid guideline “managing the long-term effects of COVID-19” by measuring the use of Post-COVID syndrome diagnosis and referral codes in the pathway.

Method

With the approval of NHS England we used routine clinical data from the OpenSafely-EMIS/-TPP platforms. Counts of Post-COVID syndrome diagnosis and referral codes were generated from a cohort of all adults, establishing numbers of diagnoses and referrals following diagnosis. The relationship between Post-COVID syndrome diagnosis and referral codes was explored with reference to NICE’s rapid guideline.

Results

Of over 45 million patients, 69,220 (0.15%) had a Post-COVID syndrome diagnostic code, and 67,741 (0.15%) had a referral code. 78% of referral codes did not have an associated diagnosis code. 79% of diagnosis codes had no subsequent referral code. Only 18,633 (0.04%) had both. There were higher rates of both diagnosis and referral in those who were more deprived, female and some ethnic groups.

Discussion

This study demonstrates variation in diagnosis and referral coding rates for Post-COVID syndrome across different patient groups. The results, with limited crossover of referral and diagnostic codes, suggest only one type of code is usually recorded. Recording one code limits the use of routine data for monitoring Post-COVID syndrome diagnosis and management, but suggests several areas for improvement in coding. Post-COVID syndrome coding, particularly diagnosis coding, needs to improve before administrators and researchers can use it to evaluate care pathways.
Can artificial intelligence help a clinical laboratory to draw useful information from limited data sets ? Application to Mixed Connective Tissue Disease
Authors: Bertin Daniel , Bongrand Pierre , Bardin Nathalie
Published: May 2023

Diagnosis is a key step of patient management. During decades, refined decision algorithms and numerical scores based on conventional statistic tools were elaborated to ensure optimal reliability. Recently, a number of machine learning tools were developed and applied to process more and more extensive data sets, including up to million of items and yielding sophisticated classification models. While this approach met with impressive efficiency in some cases, practical limitations stem from the high number of parameters that may be required by a model, resulting in increased cost and delay of decision making. Also, information relative to the specificity of local recruitment may be lost, hampering any simplification of universal models. Here, we explored the capacity of currently available artificial intelligence tools to classify patients found in a single health center on the basis of a limited number of parameters. As a model, the discrimination between systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) on the basis of thirteen biological parameters was studied with eight widely used classifiers. It is concluded that classification performance may be significantly improved by a knowledge-based selection of discriminating parameters.
Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor PD Progression
Authors: Brumm Michael C. , Siderowf Andrew , Simuni Tanya , Burghardt Elliot , Choi Seung Ho , Caspell-Garcia Chelsea , Chahine Lana M. , Mollenhauer Brit , Foroud Tatiana , Galasko Douglas , Merchant Kalpana , Arnedo Vanessa , Hutten Samantha J. , O’Grady Alyssa N. , Poston Kathleen L. , Tanner Caroline M. , Weintraub Daniel , Kieburtz Karl , Marek Kenneth , Coffey Christopher S.
Published: May 2023

Background

Identifying a meaningful progression metric for Parkinson’s disease (PD) that reflects heterogeneity remains a challenge.

Objective

To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.

Methods

Using data from the Parkinson’s Progression Markers Initiative (PPMI)de novoPD cohort, we monitored 25 milestones across six domains (“walking and balance”; “motor complications”; “cognition”; “autonomic dysfunction”; “functional dependence”; “activities of daily living”). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression.

Results

Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at thenextannual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p<0.0001), greater MDS-UPDRS total scores (p<0.0001), higher GDS-15 depression scores (p=0.0341), lower dopamine transporter binding (p=0.0043), and lower CSF total α-synuclein levels (p=0.0033). Symptomatic treatment was not significantly associated with reaching a milestone (p=0.1639).

Conclusions

Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
Antimicrobial peptide glatiramer acetate targetsPseudomonas aeruginosalipopolysaccharides to breach membranes without altering lipopolysaccharide modification
Authors: Murphy Ronan A. , Pizzato Jade , Cuthbertson Leah , Sabnis Akshay , Edwards Andrew , Nolan Laura M. , Vorup-Jensen Thomas , Larrouy-Maumus Gerald , Davies Jane C.
Published: May 2023

Antimicrobial peptides (AMPs) are key components of innate immunity across all kingdoms of life. Both natural and synthetic AMPs are receiving renewed attention in the efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogenPseudomonas aeruginosais one of the most concerning infectious bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and are associated with increased morbidity and mortality. Cationic AMPs exploit the negative charge of lipopolysaccharides (LPS) onP. aeruginosato bind to and disrupt the bacterial membrane(s) and cause lethal damage.P. aeruginosamodifies its LPS, via environmental or genetic factors, to neutralise the charge of the cell and evade AMP killing. Free-LPS is also a component of CF sputum, as is anionic extracellular DNA (eDNA), each of which can bind AMPs by electrostatic interaction. Both free LPS and eDNA also feed into pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer of glycine, lysine, alanine, and tyrosine and used as drug in the treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin againstP. aeruginosafrom CF, functioning via bacterial membrane disruption. Here, we demonstrate direct binding and sequestration/neutralisation ofP. aeruginosaLPS in keeping with GA’s ability to disrupt the outer membrane. Binding and neutralisation of eDNA was also seen. At CF-relevant concentrations, however, neither strongly inhibited membrane disruption by GA. Furthermore, in both type strains and clinical CF isolates ofP. aeruginosa, exposure to GA did not result in increased modification of the Lipid A portion of LPS or in increased expression of genetically encoded systems involved in AMP sensing and LPS modification. With this low selective pressure onP. aeruginosafor known AMP resistance mechanisms, the potential to neutralise pro-inflammatory CF sputum components, as well as the previously described enhancement of antibiotic function, GA is a promising candidate for drug repurposing.
Ecological monitoring using Collembola metabarcoding with extremely low bycatch amplification
Authors: Pedro Pedro M. , Cullen Laury , Prado Fabiana , Uezu Alexandre , Piper Ross , Faria Christiana M.A. , Knogge Christoph , Pepe Razzolini Maria Tereza , Paiva Marcela B. , Dropa Milena , Silva Miriam , Rech Tatiane Cristina , Püttker Thomas
Published: May 2023

Collembola are used widely to monitor soil health and functional parameters. Recent developments in high throughput sequencing (especially metabarcoding) have substantially increased their potential for these ends. Collembola are especially amenable to metabarcoding because of their small size, high abundance, and ubiquity in most habitat types. However, most Collembola sampling protocols collect a substantial and highly varied bycatch that can be a considerable impediment to metabarcoding, especially because of data lost to non-target species. We designed a primer set amplifying the D2 expansion segment of ribosomal DNA that is highly conserved across Collembola and successfully excludes from amplification nearly all other invertebrate taxa. We tested the diagnostic power of the primer set by clearly distinguishing Collembola communities between forest sites with differing habitat qualities in São Paulo State, Brazil. The oligos successfully amplified targets from all Collembola orders previously encountered in the sampling locations, with no non-target amplification, and also excluded the closely related Protura and Diplura. Alpha diversity (OTU count) and phylogenetic diversity was significantly higher in high quality habitats. Moreover, the beta diversity indices successfully differentiated high and low-quality habitats. This new addition to the biomonitoring toolbox greatly increases the accessibility of Collembola metabarcoding for various types of habitat assessments.
Climatic niche differentiation between native and non-native ranges is widespread in Ponto-Caspian amphipods
Authors: Šidagytė-Copilas Eglė , Copilaș-Ciocianu Denis
Published: May 2023

Niche conservatism posits that a species’ non-native populations establish in areas that match the native environmental conditions. Although the Ponto-Caspian region is a major source of inland aquatic alien species, the extent to which their climatic niches diverged between the invasive and native ranges remains poorly understood.

Using an n-dimensional hypervolume approach, we quantified climatic niche overlap and inferred patterns of niche differentiation (shift, contraction, or expansion) among native and invaded ranges for 12 widespread Ponto-Caspian amphipod species (six genera in three families).

Our results show that all investigated species experience substantially different climatic conditions in the invaded range. The invasive niche either contracted (five species), shifted (four species), expanded and shifted (two species), or shifted and contracted (one species) relative to the native niche.

We conclude that although the focal taxa share a common geographic origin and evolutionary history, they exhibit disparate patterns of climatic niche change outside the native range. The niche conservatism hypothesis receives mixed support given that half of the studied species underwent niche shifts/expansion. Furthermore, congeners exhibited both identical and contrasting patterns of niche differentiation, suggesting a limited phylogenetic effect.

The uncovered diversity of niche dynamics among closely related species indicates that each has a unique potential for invasiveness and long-term persistence. This has important implications for predicting invasion risk and refining management strategies.
Generation and characterization of aDkk4-Creknock-in mouse line
Authors: Khatif Houda , Bazzi Hisham
Published: May 2023

Ectodermal appendages in mammals, such as teeth, mammary glands, sweat glands and hair follicles, are generated during embryogenesis through a series of mesenchymal-epithelial interactions. Canonical Wnt signaling and its inhibitors are implicated in the early steps of ectodermal appendage development and patterning. To study the activation dynamics of the Wnt target and inhibitorDickkopf4(Dkk4) in ectodermal appendages, we used CRSIPR/Cas9 to generate aDkk4-Creknock-in mouse (Mus musculus) line, where theCrerecombinase cDNA replaces the expression of endogenousDkk4. UsingCrereporters, theDkk4-Creactivity was evident at the prospective sites of ectodermal appendages, overlapping with theDkk4mRNA expression. Unexpectedly, a predominantly mesenchymal cell population in the embryo posterior also showedDkk4-Creactivity. Lineage-tracing suggested that these cells are likely derived from a fewDkk4-Cre-expressing cells in the epiblast at early gastrulation. Finally, our analyses ofDkk4-Cre-expressing cells in developing hair follicle epithelial placodes revealed intra- and inter-placodal cellular heterogeneity, supporting emerging data on the positional and transcriptional variability in placodes. Collectively, we propose the newDkk4-Creknock-in mouse line as a suitable model to study Wnt and DKK4 inhibitor dynamics in early mouse development and ectodermal appendage morphogenesis.
Tight junctions regulate lumen morphology via hydrostatic pressure and junctional tension
Authors: Mukenhirn Markus , Wang Chen-Ho , Guyomar Tristan , Bovyn Matthew J. , Staddon Michael F. , Maraspini Riccardo , Lu Linjie , Martin-Lemaitre Cecilie , Sano Masaki , Hiraiwa Tetsuya , Riveline Daniel , Honigmann Alf
Published: May 2023

Formation of fluid filled lumen by epithelial tissues is a fundamental process for organ development. How epithelial cells regulate the hydraulic and cortical forces to control lumen morphology is not completely understood. Here, we quantified the mechanical role of tight junctions in lumen formation using genetically modified MDCKII cysts. We found that the paracellular ion barrier formed by claudin receptors is not required for hydraulic inflation of lumen. However, depletion of the zonula occludens scaffold resulted in lumen collapse and folding of apical membranes. Combining quantitative measurements and perturbations of hydrostatic lumen pressure and junctional tension with modelling, we were able to predict lumen morphologies from the pressure-tension force balance. We found that in MDCK tissue the tight junction promotes formation of spherical lumen by decreasing cortical tension via inhibition of myosin. In addition, we found that the apical surface area of cells is largely uncoupled from lumen volume changes, suggesting that excess apical area contributes to lumen opening in the low-pressure regime. Overall, our findings provide a mechanical understanding of how epithelial cells use tight junctions to modulate tissue and lumen shape.
Grazing of the free-living filamentous brown seaweed,Pilayella littoralis, by the amphipodGammarus tigrinis
Authors: Miller Steven L. , Wilce Robert T.
Published: May 2023

Pilayella littoralisis a common brown alga with a cosmopolitan distribution. A distinct form of the alga is found free-living in Nahant Bay, Massachusetts. Characteristics that distinguish the free-living form include radial branching that results in a ball-like morphology, reproduction by fragmentation of filaments rather than by spores, and year-round persistence of the population. The amphipodGammarus tigrinisis frequently found within the floating drifts ofP. littoralis. We conducted gut content analyses to document thatG. tigrinisconsumesP. littoralis. Culture studies revealed that ingestedP. littoraliscould survive and grow from fecal pellets produced byG. tigrinis. In addition, inefficient grazing produces vegetative fragments (propagules) that can increase numbers within the free-living population. δ13C values for the amphipods andP. littoralisaveraged -17.4 o/oo and -17.7 o/oo, respectively, suggesting thatG. tigrinisacquires most of its carbon fromP. littoralis.
NMA1982 is a Novel Phosphatase and Potential Virulence Factor inNeisseria meningitidis
Authors: Wu Shuangding , Coureuil Mathieu , Nassif Xavier , Tautz Lutz
Published: May 2023

Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase fromNeisseria meningitidis, the causative agent of meningitis and meningococcal septicemia. The overall fold of NMA1982 closely resembles that of protein tyrosine phosphatases (PTPs). However, the hallmark C(X)5R PTP signature motif, containing the catalytic cysteine and invariant arginine, is shorter by one amino acid in NMA1982. This has cast doubt about the catalytic mechanism of NMA1982 and its assignment to the PTP superfamily. Here, we demonstrate that NMA1982 indeed employs a catalytic mechanism that is specific to PTPs. Mutagenesis experiments, transition state inhibition, pH-dependence activity, and oxidative inactivation experiments all support that NMA1982 is a genuine phosphatase. Importantly, we show that NMA1982 is secreted byN. meningitidis, suggesting that this protein is a potential virulence factor. Future studies will need to address whether NMA1982 is indeed essential forN. meningitidissurvival and virulence. Based on its unique active site conformation, NMA1982 may become a suitable target for developing selective antibacterial drugs.
Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation
Authors: Amir Saira , Arowolo Olatunbosun , Mironova Ekaterina , McGaunn Joseph , Oluwayiose Oladele , Sergeyev Oleg , Pilsner J. Richard , Suvorov Alexander
Published: May 2023

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Raptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging – sperm DNA methylome rejuvenation, and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Ethics statement

All procedures followed the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the approval for this study was received from the Institutional Animal Care and Use Committee at University of Massachusetts, Amherst.
Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability
Authors: Lear Bo P. , Thompson Elizabeth A.N. , Rodriguez Kendra , Arndt Zachary P. , Khullar Saniya , Klosa Payton C. , Lu Ryan J. , Morrow Christopher S. , Risgaard Ryan , Peterson Ella R. , Teefy Brian B. , Bhattacharyya Anita , Sousa Andre M.M. , Wang Daifeng , Benayoun Bérénice A. , Moore Darcie L.
Published: May 2023

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development.

One-Sentence Summary:Directly-reprogrammed human neurons demonstrate a developmental decrease in neurite growth ability.
The transcription factor bZIP11 acts antagonistically with trehalose 6-phosphate to inhibit shoot branching
Authors: Hellens A. M. , Kreisz P. , Humphreys J. L. , Feil R. , Lunn J.E. , Dröge-Laser W. , Beveridge C. A. , Fichtner F. , Weiste C. , Barbier F. F.
Published: May 2023

The ontogenetic regulation of shoot branching allows plants to adjust their architecture in accordance with the environment. This process is due to the regulation of axillary bud outgrowth into branches, which can be induced by increasing sugar availability to the buds through decapitation of the shoot tip. Different sugar signalling components have been identified in the induction of shoot branching. However, the molecular components that maintain bud dormancy in response to sugar starvation remain largely unknown. Here, we show at the genetic level that basic leucine zipper 11 (bZIP11), a transcription factor that plays important roles in response to sugar starvation in plants, inhibits shoot branching inArabidopsis thaliana. Physiology experiments demonstrated that bZIP11 protein levels are decreased by decapitation. Molecular and genetic evidence suggests that bZIP11 acts in a negative feedback loop with trehalose 6-phosphate (Tre6P), a sugar signal that promotes shoot branching. Our data also suggest that the central energy sensor SUCROSE NON-FERMENTING 1 RELATED KINASE1 (SnRK1), alleviates the inhibitory effect of Tre6P on bZIP11 protein accumulation and inhibits shoot branching. Altogether, these data provide a working model that involves bZIP11, Tre6P and SnRK1 in the regulation of shoot branching.
A Standardized Antiviral Pipeline for Human Norovirus in Human Intestinal Enteroids Demonstrates No Antiviral Activity of Nitazoxanide
Authors: Lewis Miranda A. , Cortés-Penfield Nicolás W. , Ettayebi Khalil , Patil Ketki , Kaur Gurpreet , Neill Frederick H. , Atmar Robert L. , Ramani Sasirekha , Estes Mary K.
Published: May 2023

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within three days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we established a standardized pipeline for antiviral testing using multiple human small intestinal enteroid (HIE) lines representing different intestinal segments and evaluated whether nitazoxanide inhibits replication of 5 HuNoV strainsin vitro. Nitazoxanide did not exhibit high selective antiviral activity against any HuNoV strains tested, indicating it is not an effective antiviral for norovirus infection. HIEs are further demonstrated as a model to serve as a pre-clinical platform to test antivirals against human noroviruses to treat gastrointestinal disease.
Differential functional coupling in Gp130-JAK complexes expands the plasticity of the interleukin-6 signaling axis
Authors: McFarlane Alison , Bellón Junel Sotolongo , Meyer Thomas , Pohler Elizabeth , Piehler Jacob , Moraga Ignacio
Published: May 2023

Cytokines dimerize/oligomerize surface receptors to activate signaling. While cytokine receptors preferentially bind only one member of the JAK family, ancestral cytokine receptors, such as Gp130, promiscuously recruit different JAKs to elicit their activities. Here, we have explored how the identity of JAKs in Gp130 signaling complexes can regulate functional outcomes. Using a synthetic biology approach, we show that Gp130 bound to different JAKs propagates distinct STAT activation profiles. While Gp130-JAK1 complexes activated both, STAT1 and STAT3 very potently, Gp130-JAK2 complexes exhibited a clear preference for STAT3 activation. Gp130-TYK2 complexes triggered overall weaker signaling but with diminished STAT specificity. The three JAKs competed for binding to Gp130 and led to differential activation of phospho-Tyr in the Gp130 intracellular domain. JAK1, JAK2 and to a lower extent TYK2 bound with comparable affinities to Gp130, and in response to IL-6 stimulation efficiently drove Gp130 dimerization. However, the three JAKs differentially affected Gp130 surface expression, identifying JAK-dependent receptor trafficking as a critical determinant of signaling plasticity. Our results provide new mechanistic insights into how differential functional coupling in Gp130-JAK complexes translates into unique signaling signatures that likely contribute to its large functional diversity.
Fed-ComBat: A Generalized Federated Framework for Batch Effect Harmonization in Collaborative Studies
Authors: Silva Santiago , Oxtoby Neil , Altmann Andre , Lorenzi Marco
Published: May 2023

In neuroimaging research, the utilization of multi-centric analyses is crucial for obtaining sufficient sample sizes and representative clinical populations. Data harmonization techniques are typically part of the pipeline in multi-centric studies to address systematic biases and ensure the comparability of the data. However, most multi-centric studies require centralized data, which may result in exposing individual patient information. This poses a significant challenge in data governance, leading to the implementation of regulations such as the GDPR and the CCPA, which attempt to address these concerns but also hinder data access for researchers. Federated learning offers a privacy-preserving alternative approach in machine learning, enabling models to be collaboratively trained on decentralized data without the need for data centralization or sharing.

In this paper, we present Fed-ComBat, a federated framework for batch effect harmonization on decentralized data. Fed-ComBat extends existing centralized linear methods, such as ComBat and distributed as d-ComBat, and nonlinear approaches like ComBat-GAM in accounting for potentially nonlinear and multivariate covariate effects. By doing so, Fed-ComBat enables the preservation of nonlinear covariate effects without requiring centralization of data and without prior knowledge of which variables should be considered nonlinear or their interactions, differentiating it from ComBat-GAM. We assessed Fed-ComBat and existing approaches on simulated data and multiple cohorts comprising healthy controls (CN) and subjects with various disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and autism spectrum disorder (ASD).

Results indicate that Fed-ComBat outperforms centralized ComBat in the presence of nonlinear effects and is comparable to centralized methods such as ComBat-GAM. Using synthetic data, Fed-ComBat is able to better reconstruct the target unbiased function by 35% (RMSE = 0.5952) with respect to d-ComBat (RMSE = 0.9162) and 12% with respect to our proposal to federate ComBat-GAM, d-ComBat-GAM (RMSE= 0.6751) and exhibits comparable results on MRI-derived phenotypes to centralized methods as ComBat-GAM without the need of prior knowledge on potential nonlinearities.
A compact gas attenuator for the SwissFEL ATHOS beamline realized using additive manufacturing
Authors: Pradervand Claude , Rosenberg Colette , Eckerlin Hans-Jörg , Schnorr Kirsten , Al Haddad Andre , Wiegand Peter , Hess Christoph , Gaiffi Nazareno , Patthey Luc
Published: May 2023

Gas attenuators are important devices providing accurate variation of photon intensity for soft X-ray beamlines. In the SwissFEL ATHOS beamline front-end the space is very limited and an innovative approach has been taken to provide attenuation of three orders of magnitude up to an energy of 1200 eV. Additive manufacturing of a differential pumping system vacuum manifold allowed a triple pumping stage to be realized in a space of less than half a meter. Measurements have shown that the response of the device is as expected from theoretical calculations.
Product innovation research over the past 60 years: a bibliometric analysis of intellectual structure and emergent trends
Authors: Aboelmaged Mohamed , Bani-Melhem Shaker , Al-Hawari Mohd Ahmad , Ali Imran
Published: May 2023

Purpose

Literature on product innovation (PI) has witnessed tremendous growth over the past 60 years. Yet, there has been a dearth of a comprehensive review of the extant PI research maintaining the breadth and depth of the topic. To seal this gap, this paper aims to explore the intellectual foundations and emergent trends in 2,588 research papers on PI from 1962 to 2022.

Design/methodology/approach

The paper adopts a bibliometric analysis approach via visualization maps of prolific contributions, co-citation, co-occurrence and thematic networks.

Findings

Emerging streams, frontiers and hotspots in PI research are revealed and a knowledge graph is developed. The review provides a broad spectrum of opportunities that enrich imminent research to better inform business decisions.

Practical implications

The review addresses 20 research questions associated with barely examined areas in PI research that require further analysis in imminent research.

Originality/value

To the best of the authors' knowledge, this is the first review that comprehensively synthesizes the intersected knowledge base of PI research using bibliometric analysis of a vast number of documents within a long time span.
A virtual reality-based constructability index for construction projects
Authors: Qasem Altayeb , Almohassen Abdulaziz Saud
Published: May 2023

Purpose

This study aims to develop a constructability index (CI) that can ease the construction activities in a project based on the contractors’ experience and resources. The proposed CI is a vital decision support tool that quantifies the difficulty level for the contractor to execute certain activities with the contingency of other project elements. The virtual reality (VR) technology was used to provide additional data, communicate the contingency impact of other project elements on specific activities and provide sequential execution data to the contractors. This can minimize the risk of not being able to execute various activities on time and within the budget.

Design/methodology/approach

The VR-based CI was developed through two steps. Step 1 was to identify the factors affecting constructability by exploring the literature and consulting local construction experts. These factors were then organized through a hierarchy of main factors and subfactors and validated by local experts through predesigned surveys. The factors were classified into VR dependent or non-VR independent, and their relative weights were calculated using the analytical hierarchy process along with their reliability, which was determined using Cronbach’s alpha approach. Step 2 was to define the attributes for the constructability factors defined in Step 1 using the Multi Attribute Utility Theory to quantify the contractor’s compliance level of these factors by giving them the appropriate score. The utility factors for the VR-independent factors were obtained through standards, literature and local surveys, and they were quantified on a 1–10 scale. However, the VR-dependent factors were given their corresponding scores using the developed VR navigation environment generated by integrating Autodesk Revit and Navisworks software. Accordingly, the CI for each activity was evaluated, and the overall CI for the project was calculated by aggregating the CIs for all activities.

Findings

The developed CI quantifies the contractor’s ability to execute construction projects and addresses the lack of communication and coordination between the various construction units in the planning phase itself. Moreover, it can resolve possible hard (physical) and soft (time) construction clashes and minimize their impacts on project schedule and budget. Among the relative weights of the identified factors, prefabrication of building components was found to have the highest effect on constructability. Furthermore, applying the developed VR-CI, a real project showed that the utility values of the main factors quantified on a ten-point scale were between 6 and 9, which means routine supervisions and monitoring are required.

Originality/value

Though the concepts of constructability and VR have been used in different contexts, their integration to develop a comprehensive CI for the building construction industry is a unique contribution, which has not been reported previously.
Prioritizing factors for effective strategy implementation in small and medium-size organizations
Authors: López-Torres Jose F. , Sánchez-García Jacqueline Y. , Núñez-Ríos Juan E. , López-Hernández Carlos
Published: May 2023

Purpose

Organizations depend on multiple factors to maintain competitiveness and continuously adapt to the environment. Managers must know how to implement strategies while motivating the commitment of those involved. This study aims to present a model for prioritizing factors to promote effective strategy implementation in small- and medium-sized companies.

Design/methodology/approach

The authors adopted a systemic approach to articulate two instruments: social network analysis to identify the components that could affect strategy implementation, designing a conceptual model with this information, and analytical hierarchy process to validate the resulting construct.

Findings

The factors for effectively implementing strategies relate to the need for reinforcement, commitment, organizational culture, managerial skills, clear communication and involvement to reduce inconsistencies between the expected and current organizational state without neglecting coordination and management mechanisms.

Research limitations/implications

This work is limited to organizational matters. This study was conducted in collaboration with medium-sized Mexican companies with the participation of 94 managers with 10 years of experience. Although the results are mathematically rigorous, increasing the number of participants could enhance the approach to the problem.

Practical implications

This study could encourage academics and practitioners to target resources more accurately and improve organizational relationships to bridge the gap between strategic planning and practical implementation.

Originality/value

This study contrasts with previous research in proposing a systemic perspective that integrates participants’ experiences, developing a construct to determine and prioritize the factors to be addressed in strategy implementation. Therefore, this work invites the adoption of the proposed method as a complementary path to enrich academic and professional exchange.
The start-up's roadmap to private equity financing: substituting discounts with a premium in valuation for growth
Authors: Giakoumelou Anastasia , Salvi Antonio , Kvasova Olga , Rizomyliotis Ioannis
Published: May 2023

Purpose

Access to financing is a key success factor for start-ups. High failure rates, long payback periodse and asymmetries lead to conservative pricing and valuation discounts. The authors examine financial marketing and contingent factors, as enablers of a “patent premium” by private equity (PE) investors targeting start-ups in their growth and expansion stages.

Design/methodology/approach

Drawing from the contingency, innovation and signaling theories, the authors collect patent records for Italian start-ups in which a higher than 30% stake was acquired by PE investors during the period 2014–2020. The authors apply a generalized linear model with a logit link and robust clustered error to test the key relationships and control for endogeneity with a Heckman two-stage selection model.

Findings

Findings indicate start-ups’ access to financing is significantly impacted by marketing constructs adopted in the operation. Innovation alone does not suffice to determine a valuation premium, unless contingent on the promotion of its product, the placement -investors targeted-of the equity, brand equity levers of previous ownership and marketing competence backing the deal.

Originality/value

The authors provide new insights in the marketing-finance interface, highlighting levers that reassure investors and enable monetizing innovation in start-ups that are still privately held. The authors bridge a gap in literature that has mainly focused on venture capital and innovation financing in the open market, as well as a significant gap regarding the marketing design of private equity placements.
Fostering extra-role green behavior through green HRM practices: mediating role of green absorptive capacity
Authors: Sarmad Muhammad , Pirzada Muhammad Ahmed , Iqbal Rimsha
Published: May 2023

Purpose

The green aspects in current management practices are strongly emphasized for sustainable and environment friendly business operations. Thus, building on ability-motivation-opportunity (AMO) theory, this study aims to test the mediating role of green absorptive capacity in the relationship between green human resources management (GHRM) practices (i.e., green training and development, and green performance management) and organizational citizenship behavior towards environment (OCBE).

Design/methodology/approach

Using a paper-pencil survey, the authors collected data from 170 middle-tier officers working in cement industry of Pakistan. Structural equation modeling technique was applied for data analysis through Smart-PLS.

Findings

Results indicated that GHRM practices significantly influence OCBE and green absorptive capacity partially mediates the relationship between GHRM practices and OCBE.

Originality/value

This study offers new theoretical and practical insights by empirically investigating the mediating role of green absorptive capacity between GHRM practices and OCBE through the lens of AMO theory. Furthermore, this study contributed in disclosing the predictors of OCBE through intervening mechanism in manufacturing sector of developing country for sustainable outcomes.
Validation of the Arabic version of the refugee health screener-13 among postpartum Syrian refugees in Lebanon
Authors: Alnaji Nada A. , Struwe Leeza A. , Bagenda Danstan
Published: May 2023

Purpose

Refugee mothers are at a significantly increased risk of suffering from postpartum depression. However, available tools to screen for it often use a Western paradigm of mental health, which may not be culturally appropriate, and may not account for the background stress experienced by refugees. The purpose of this study is to test and validate refugee health screener-13 (RHS-13), which was developed by consultation with refugees from different backgrounds among a group of Syrian refugee mothers living in Beqaa’s valley in Lebanon.

Design/methodology/approach

The tool was tested on a sample of 103 women. Internal consistency of the items for each subscale was assessed using Cronbach’s alpha. An interitem correlation was performed to examine the most correlated items on the scale. Pearson correlation coefficient was calculated between each subscale and its diagnostic proxy. To find the best fit cutoff point between sensitivity and 1-specificity, ROC curves were used.

Findings

RHS-13 is a reliable and valid tool to detect depression and anxiety among postpartum Syrian mothers (internal consistency 0.803, correlation with patient health questionnaire: 0.63 and correlation with generalized anxiety disorder-7: 0.73). The best fit cutoff points were 12, 15 and 25, indicating the severity of symptoms from mild to severe, respectively.

Originality/value

RHS-13 is a valid tool among postpartum refugees in Lebanon and can be used by primary care physicians, mental health providers and social workers working with refugees from the Middle East to screen mothers for depression and anxiety.