bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Intensification Treatment in Patients with Rectal Adenocarcinoma – A Standardization of Clinical Practice
Authors: Leal-Costa Luísa , Silva Diana , Baptista Carlota , Bizarro Rita , Machete Madalena , Simões Pedro , Faria Ana , Teixeira José Alberto
Published: January 2023

Neoadjuvant radiotherapy with concurrent fluoropyrimidines followed by surgery is considered the standard-of-care in locally advanced rectal cancer (LARC). Neoadjuvant chemo-radiotherapy (CRT) is associated with a pathological complete response (pCR) rate of 11-18%. Intensification of neoadjuvant treatment can lead to higher rates of tumor resectability and pCR, although the best therapeutic sequence is unknown.

This is a prospective, single arm study which aims to standardize institutional clinical practice in accordance with international recommendations. Patients with LARC received neoadjuvant intensive treatment with concurrent CRT followed by 12 weeks of consolidation chemotherapy (ChT) with CAPOX or mFOLFOX6. Clinical response was accessed by magnetic resonance imaging (MRI) at 10 weeks, 14 weeks, and 18 weeks. If complete clinical response (cCR) was obtained, awatch-and-wait(W&W) strategy was offered; otherwise, surgery was performed. The primary endpoint was to evaluate clinical response rate after 10 weeks of intensification treatment, and its comparison with historical data. Key secondary endpoints included clinical response rate at 14 and 18 weeks, rate of patients who enter W&W strategy, rate of pCR in patients who undergo surgery, recurrence free survival (RFS), overall survival (OS), and rate of adverse effects. We present efficacy and safety preliminary results one year from the start of the study.

Six patients with LARC were included. Three had a tumour in the low-rectum, two in middle-rectum and one in high-rectum. At initial magnetic resonance imaging (MRI), two had cT2, three had cT3 and one had cT4; three had cN1 and one cN2; two patients had extramural venous invasion (EMVI+) and one had mesorectal fascia involvement (MRF+).

After CRT, all patients started consolidation ChT. The most common grade ≥3 AEs were neutropenia, nausea, and diarrhoea. There were no dose-limiting toxicities and all patients completed treatment. MRI at 10 weeks showed a tumour regression grade (TRG) 2 in three patients, TRG3 in two patients and TRG4 in one patient. Two patients are in the W&W surveillance protocol; one is awaiting MRI at 18 weeks; another patient awaits surgery; and of the two patients already underwent surgery, one had a ypT3N1 and the other had complete pathological response (pCR). To this date there are no recurrence or death events.

These preliminary results suggests tolerability and feasibility of a neoadjuvant intensification treatment in patients with LARC.

Categories

rectal adenocarcinoma, oncology
Meta-evaluation of a whole systems programme, ActEarly: A study protocol
Authors: Mansukoski Liina , Lockyer Bridget , Creaser Amy , Sheringham Jessica , Sheard Laura , Garnett Philip , Yang Tiffany , Cookson Richard , Albert Alexandra , Islam Shahid , Shore Robert , Khan Aiysha , Twite Simon , Dawson Tania , Iqbal Halima , Skarda Ieva , Villadsen Aase , Asaria Miqdad , West Jane , Sheldon Trevor , Wright John , Bryant Maria
Published: January 2023

Introduction

Living in an area with high levels of child poverty predisposes children to poorer mental and physical health. ActEarly is a 5-year research programme that comprises a large number of interventions (>20) with citizen science and co-production embedded. It aims to improve the health and well-being of children and families living in two areas of the UK with high levels of deprivation; Bradford in West Yorkshire, and the London Borough of Tower Hamlets. This protocol outlines the meta-evaluation (an evaluation of evaluations) of the ActEarly programme from a systems perspective, where individual interventions are viewed as events in the wider policy system across the two geographical areas. It includes investigating the programme’s impact on early life health and well-being outcomes, interdisciplinary prevention research collaboration and capacity building, and local and national decision making.

Methods

The ActEarly meta-evaluation will follow and adapt the five iterative stages of the ‘Evaluation of Programmes in Complex Adaptive Systems’ (ENCOMPASS) framework for evaluation of public health programmes in complex adaptive systems. Theory-based and mixed-methods approaches will be used to investigate the fidelity of the ActEarly research programme, and whether, why and how ActEarly contributes to changes in the policy system, and whether alternative explanations can be ruled out. Ripple effects and systems mapping will be used to explore the relationships between interventions and their outcomes, and the degree to which the ActEarly programme encouraged interdisciplinary and prevention research collaboration as intended. A computer simulation model (“LifeSim”) will also be used to evaluate the scale of the potential long-term benefits of cross-sectoral action to tackle the financial, educational and health disadvantages faced by children in Bradford and Tower Hamlets. Together, these approaches will be used to evaluate ActEarly’s dynamic programme outputs at different system levels and measure the programme’s system changes on early life health and well-being.

Discussion

This meta-evaluation protocol presents our plans for using and adapting the ENCOMPASS-framework to evaluate the system-wide impact of the early life health and well-being programme, ActEarly. Due to the collaborative and non-linear nature of the work, we reserve the option to change and query some of our evaluation choices based on the feedback we receive from stakeholders to ensure that our evaluation remains relevant and fit for purpose.
High-dimensional phenotyping to define the genetic basis of cellular morphology
Authors: Tegtmeyer Matthew , Arora Jatin , Asgari Samira , Cimini Beth A. , Peirent Emily , Liyanage Dhara , Way Gregory , Weisbart Erin , Nathan Aparna , Amariuta Tiffany , Eggan Kevin , Haghighi Marzieh , McCarroll Steven A. , Carpenter Anne E. , Singh Shantanu , Nehme Ralda , Raychaudhuri Soumya
Published: January 2023

The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combined genomic and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identified novel associations between rare protein altering variants inWASF2, TSPAN15, andPRLRwith several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirmed their role in cell morphology. Analysis of common variants yielded one significant association and nominated over 300 variants with suggestive evidence (P<10-6) of association with one or more morphology traits. Our results showed that, similar to other molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.
Identification, characterisation and recombinant expression of flavonoid 3’,5’-hydroxylases and cytochrome P450 reductases fromVacciniumspecies
Authors: Kukk Kaia
Published: January 2023

Flavonoid 3’,5’-hydroxylases (F3′5′Hs) play a key role in biosynthesis of blue coloured anthocyanin complexes in plants. Thus these proteins have potential application in the development of a natural blue coloured food dye using microbial cell factories. However, F3′5′Hs are membrane proteins that require a redox partner, NADPH-cytochrome P450 reductase (CPR). The aim of the research was to identify F3′5′H sequences fromVacciniumspecies plants and express the respective proteins in yeast to test their potential in biotechnological production of precursors of anthocyanins. In this study, novel coding DNA sequences of F3′5′Hs fromVaccinium myrtillusandVaccinium uliginosum, and two CPRs fromV. myrtilluswere identified and characterised. The newly obtained proteins and F3′5′H fromVaccinium corymbosumand CPR fromHelianthus annuuswere expressed inPichia pastoris. Addition of DMSO into the culture medium increased production of F3′5′Hs and CPRs. A truncated form ofV. corymbosumF3′5′H, that lacked the predicted first N-terminal alpha helix, expressed at higher level compared to the full-length protein.VacciniumF3′5′Hs were combined with different CPRs and substrates to identify which CPR acts as a redox partner for F3′5′Hs and which substrates are preferred. Unfortunately, only substrates but not the products could be detected, indicating that the recombinant F3′5′Hs were inactive. Therefore, despite progress in protein expression,P. pastoriswas not a suitable host for producingVacciniumF3′5′Hs.
An expert-based global assessment of threats and conservation measures for subterranean ecosystems
Authors: Nanni Veronica , Piano Elena , Cardoso Pedro , Isaia Marco , Mammola Stefano
Published: January 2023

Subterranean ecosystems host unique biodiversity and deliver important services to humans. Yet, available data for subterranean ecosystems are limited in space and/or taxonomic scope and global monitoring programs are absent, preventing practitioners to develop effective conservation and management strategies. Expert opinion may help overcome some of these knowledge gaps. We designed a global survey to quantify the importance of anthropogenic impacts and conservation measures for subterranean ecosystems. We obtained 279 responses from 155 experts in different subterranean habitats, taxa, and regions. Experts perceived surface habitat change, direct habitat destruction (e.g., pollution, damming, mining), and climate change as the most relevant threats impacting subterranean ecosystems. Legislation, land protection, and education were scored as the most effective conservation measures, whereas species-level conservation was deemed less relevant. Whenever lacking hard data, expert opinion may be an effective, largely available, yet often overlooked source of information to implement timely conservation interventions for subterranean ecosystems.
Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern
Authors: Frasson Ilaria , Diamante Linda , Zangrossi Manuela , Carbognin Elena , Pietà Anna Dalla , Penna Alessandro , Rosato Antonio , Verin Ranieri , Torrigiani Filippo , Salata Cristiano , Vaccaro Lorenzo , Cacchiarelli Davide , Richter Sara N. , Montagner Marco , Martello Graziano
Published: January 2023

The high mutation rate of SARS-CoV-2 leads to emergence of several variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors – cell proteins required for viral replication - would help avoid resistance. However, whether different SARS-CoV-2 variants induce conserved cell responses and exploit the same core host factors is still unclear.

We compared three variants of concern and observed that the host transcriptional response was conserved, differing only in kinetics and magnitude. By CRISPR screening we identified the host genes required for infection by each variant: most of the identified genes were shared by multiple variants, both in lung and colon cells. We validated our hits with small molecules and repurposed FDA-approved drugs. All drugs were highly effective against all tested variants, including delta and omicron, new variants that emerged during the study. Mechanistically, we identified ROS production as a pivotal step in early virus propagation. Antioxidant drugs, such as N-acetyl cysteine (NAC), were effective against all variants both in human lung cells, and in a humanised mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.
A network based approach to identifying correlations between phylogeny, morphological traits and occurrence information of fish Species in US river basins
Authors: Tripathi Richa , Reza Amit , Su Guohuan , Mertel Adam , Calabrese Justin M.
Published: January 2023

The complex network framework has been successfully used to model interactions between entities in Complex Systems in the Biological Sciences such as Proteomics, Genomics, Neuroscience, and Ecology. Networks of organisms at different spatial scales and in different ecosystems have provided insights into community assembly patterns and emergent properties of ecological systems. In the present work, we investigate two questions pertaining to fish species assembly rules in US river basins, a) if morphologically similar fish species also tend to be phylogenetically closer, and b) to what extent are co-occurring species that are phylogentically close also morphologically similar? For the first question, we construct a network of Hydrologic Unit Code 8 (HUC8) regions as nodes with interaction strengths (edges) governed by the number of common species. For each of the modules of this network, which are found to be geographically separated, there is differential yet significant evidence that phylogenetic distance predicts morphological distance. For the second question, we construct and analyze nearest neighbor directed networks of species based on their morphological distances and phylogenetic distances. Through module detection on these networks and comparing the module-level mean phylogenetic distance and mean morphological distance with the number of basins of common occurrence of species in modules, we find that both phylogeny and morphology of species have significant roles in governing species co-occurrence, i.e. phylogenetically and morphologically distant species tend to co-exist more. In addition, between the two quantities (morphological distance and phylogentic distance), we find that morphological distance is a stronger determinant of species co-occurrences.
YAP-dependent autophagy is controlled by AMPK, SIRT1 and flow intensity in kidney epithelial cells
Authors: Claude-Taupin Aurore , Roccio Federica , Garfa-Traoré Meriem , Regnier Alice , Burtin Martine , Morel Etienne , Terzi Fabiola , Codogno Patrice , Dupont Nicolas
Published: January 2023

Shear stress generated by the urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow. Here, we show that nuclear YAP/TAZ negatively regulates autophagy machinery in kidney epithelial cells subjected to fluid flow. This crosstalk is supported by a primary cilium-dependent activation of AMPK and SIRT1, independently of the Hippo pathway. We confirmed the relevance of the YAP/TAZ-autophagy molecular dialogin vivousing a zebrafish model of kidney development and a unilateral ureteral obstruction mouse model. In addition, anin vitroassay simulating the pathological flow observed at early stages of chronic kidney disease (CKD) activated YAP, leading to a primary cilium-dependent inhibition of autophagy. Our findings demonstrate the importance of YAP/TAZ and autophagy in the translation of fluid flow into cellular and physiological responses. Dysregulation of this pathway is associated with the early onset of CKD.
Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks
Authors: Patel Dhruv , Lin Raymond , Majumder Barun , Ganusov Vitaly V.
Published: January 2023

For survival of the organism T cells must efficiently control pathogens invading different peripheral tissues but whether such control (and lack of thereof) is achieved by utilizing different movement strategies remains poorly understood. Liver-localized CD8 T cells perform correlated random walks — a type of a Brownian walk – in liver sinusoids but in some condition these T cells may also perform Levy flights – rapid and large displacements by floating with the blood flow. CD8 T cells in lymph nodes or skin also undergo Brownian walks. A recent study suggested that brain-localized CD8 T cells, specific toToxoplasma gondii, perform generalized Levy walks – a walk type in which T cells alternate pausing and displacing long distances — which may indicate that brain is a unique organ where T cells exhibit movement strategies different from other tissues. We quantified movement patterns of brain-localizedPlasmodium berghei-specific CD4 and CD8 T cells by using well-established statistical and computational methods. Interestingly, we found that T cells change their movement pattern with time since infection and that CD4 T cells move faster and turn less than CD8 T cells. Importantly, both CD4 and CD8 T cells move in the brain by correlated random walks without long displacements challenging previous observations. We have also re-analyzed the movement data of brain-localized CD8 T cells inT. gondii-infected mice and found no evidence of Levy walks. We hypothesize that the previous conclusion of Levy walks ofT. gondii-specific CD8 T cells in the brain was reached due to missing time-frames in the data that create an impression of large displacements between assumed-to-be-sequential movements. Taken together, our results suggests that movement strategies of CD8 T cells are largely similar between LNs, liver, and the brain and consistent with correlated random walks and not Levy walks.
A shift in the mechanisms controlling hippocampal engram formation during brain maturation
Authors: Ramsaran Adam I. , Wang Ying , Golbabaei Ali , Yeung Bi-ru Amy , de Snoo Mitchell L. , Rashid Asim J. , Awasthi Ankit , Lau Jocelyn , Tran Lina M. , Ko Sangyoon Y. , Abegg Andrin , Duan Lana Chunan , McKenzie Cory , Gallucci Julia , Ahmed Moriam , Kaushik Rahul , Dityatev Alexander , Josselyn Sheena A. , Frankland Paul W.
Published: January 2023

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory formation are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 by extracellular perineuronal nets which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.

One-Sentence Summary

Episodic-like memory precision requires maturation of hippocampal inhibitory interneurons by the extracellular matrix.
Ecological and life history drivers of avian skull evolution
Authors: Hunt Eloise S. E. , Felice Ryan N. , Tobias Joseph A. , Goswami Anjali
Published: January 2023

One of the most famous examples of adaptive radiation is that of the Galápagos finches, where skull morphology, particularly the beak, varies with feeding ecology. Yet increasingly studies are questioning the strength of this correlation between feeding ecology and morphology in relation to the entire neornithine radiation, suggesting that other factors also significantly affect skull evolution. Here, we broaden this debate to assess the influence of a range of ecological and life history factors, specifically habitat density, migration, and developmental mode, in shaping avian skull evolution. Using 3D geometric morphometric data to robustly quantify skull shape for 354 extant species spanning avian diversity, we fitted flexible phylogenetic regressions and estimated evolutionary rates for each of these factors across the full dataset. The results support a highly significant relationship between skull shape and both habitat density and migration, but not developmental mode. We further found heterogenous rates of evolution between different character states within habitat density, migration, and developmental mode, with rapid skull evolution in species which occupy dense habitats, are migratory, or are precocial. These patterns demonstrate that diverse factors impact the tempo and mode of avian phenotypic evolution, and that skull evolution in birds is not simply a reflection of feeding ecology.

Impact summary

Almost 200 years ago, Darwin found that the beaks of Galápagos finches were different shapes in birds with different diets. Nowadays, it is well established that phylogeny, allometry, and ecology can also be key factors in shaping skulls. Yet, the influence of specific aspects of ecology, as well as life history, on morphological evolution remain poorly constrained. Here, we examined whether three novel factors also influence the shape of bird skulls and rates of evolution: habitat density, migration, or developmental mode. To do so, we combine high resolution 3D quantification of skull shape with dense taxonomic sampling across living birds. Our analyses revealed that skull shape varies in birds based on the density of vegetation in their habitats and on the extent to which they migrate. However, how independent birds are when they are born does not appear to influence overall skull shape. Despite these differences in how much they influence the shape of the skull, habitat density, migration and life history all influence the rate at which bird skulls evolve. Birds evolved fastest if they live in densely vegetated habitats, migrate long distances, or are precocial. These results add to the growing body of evidence that skull evolution in birds is impacted by a diverse range of factors, and suggests that habitat density, migration and life history should be considered in future analyses on drivers of phenotypic evolution.
Spin-Coupled Electron Densities of Iron-Sulfur Cluster Imaged byIn SituSerial Laue Diffraction
Authors: Ren Zhong , Zhang Fan , Kang Weijia , Wang Cong , Shin Heewhan , Zeng Xiaoli , Gunawardana Semini , Bowatte Kalinga , Krauß Norbert , Lamparter Tilman , Yang Xiaojing
Published: January 2023

Iron-sulfur clusters are inorganic cofactors found in many proteins involved in fundamental biological processes including DNA processing. The prokaryotic DNA repair enzyme PhrB, a member of the protein family of cryptochromes and photolyases, carries a four-iron-four-sulfur cluster [4Fe4S] in addition to the catalytic cofactor flavin adenine dinucleotide (FAD) and a second pigment 6,7-dimethyl-8-ribityllumazine (DMRL). The light-induced redox reactions of this multi-cofactor protein complex were recently shown as two interdependent photoreductions of FAD and DMRL mediated by the [4Fe4S] cluster functioning as an electron cache to hold a fine balance of electrons. Here, we apply the more traditional temperature-scan cryo-trapping technique in protein crystallography and the newly developed technology ofin situserial Laue diffraction at room temperature. These diffraction methods in dynamic crystallography enable us to capture strong signals of electron density changes in the [4Fe4S] cluster that depict quantized electronic movements. The mixed valence layers of the [4Fe4S] cluster due to spin coupling and their dynamic responses to light illumination are observed directly in our difference maps between its redox states. These direct observations of the quantum effects in a protein bound iron-sulfur cluster have thus opened a window into the mechanistic understanding of metal clusters in biological systems.
Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity
Authors: Subhadarshini Seemadri , Sahoo Sarthak , Debnath Shibjyoti , Somarelli Jason A. , Jolly Mohit Kumar
Published: January 2023

Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra- and inter-tumoral phenotypic heterogeneity, such as IFNγ signaling and proliferative to invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Here, we integrate dynamical systems modeling with transcriptomic data analysis at bulk and single-cell levels to investigate underlying mechanisms behind phenotypic heterogeneity in melanoma and its impact on adaptation to targeted therapy and immune checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated in this process and identify the multiple “attractors” in the phenotypic landscape enabled by this network. Our model predictions about synergistic control of PD-L1 by IFNγ signaling and proliferative to invasive transition were validated experimentally in three melanoma cell lines – MALME3, SK-MEL-5 and A375. We demonstrate that the emergent dynamics of our regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them, including in response to targeted therapy and immune checkpoint inhibitors. These phenotypes have varied levels of PD-L1, driving heterogeneity in immune-suppression. This heterogeneity in PD-L1 can be aggravated by combinatorial dynamics of these regulators with IFNγ signaling. Our model predictions about changes in proliferative to invasive transition and PD-L1 levels as melanoma cells evade targeted therapy and immune checkpoint inhibitors were validated in multiple data sets fromin vitroandin vivoexperiments. Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for the treatment of metastatic melanoma. This improved understanding of crosstalk among PD-L1 expression, proliferative to invasive transition and IFNγ signaling can be leveraged to improve the clinical management of therapy-resistant and metastatic melanoma.
BRDriver: Breast Cancer Driver Gene Predictor
Authors: Perera Rajitha , Perera Roshan
Published: January 2023

The breast cancer mortality rate is high in developing countries as the early detection of cancer is deficient in patients. The identification of the genes that drive cancer is one of the major approaches in the early detection of breast cancer. Several computational tools have been developed to predict the cancer driver genes. However, there is no gold-standard method for identifying breast cancer driver genes. Therefore, this study aims to develop a model to predict high-confidence breast cancer diver genes using already-developed computational tools and already-produced breast cancer data. Primary breast cancer data were retrieved from the Cancer Genome Atlas Program (TCGA). Here we use twenty-seven different gene prediction tools that calculate each gene’s effect and variant in the primary gene dataset. The primary dataset feeds as the input for each tool. The results retrieved from each tool are recorded as the secondary dataset. The latest breast cancer driver gene set was retrieved from DriverDBv3 and included as the target attribute. Training and testing subsets were selected using k-fold cross-validation from the secondary dataset. Attributes from the secondary dataset were ranked according to their correlation with breast cancer driver genes. The ranked data were trained using different supervised machine-learning algorithms. The attributes and the learning algorithm which produced the highest classification accuracy were selected to build the new model, BReast cancer Driver (BRDriver). The new model BRDriver achieved 0.999 area under the curve and 0.999 classification accuracy on breast invasive carcinoma data. TP53 was the most predicted breast cancer drive gene (n=246) predicted by BRDriver. Interestingly, our BRDriver model predicted CDKN2A and NFE2L2 genes as new breast cancer driver genes. Furtherin vivoandin vitrostudies are required to determine whether these genes are indeed cancer-driver genes. Many computational tools developed to identify the cancer driver genes and variants. A few methodologies were developed to combine these tools and increase efficiency for detecting breast cancer driver genes. Our BRDriver overcomes the difficulties and produces high-confidence breast cancer driver genes.
LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome
Authors: Busley Alexandra Viktoria , Gutiérrez-Gutiérrez Óscar , Hammer Elke , Koitka Fabian , Mirzaiebadizi Amin , Steinegger Martin , Pape Constantin , Böhmer Linda , Schroeder Henning , Kleinsorge Mandy , Engler Melanie , Cirstea Ion Cristian , Gremer Lothar , Willbold Dieter , Altmüller Janine , Marbach Felix , Hasenfuss Gerd , Zimmermann Wolfram-Hubertus , Ahmadian Mohammad Reza , Wollnik Bernd , Cyganek Lukas
Published: January 2023

Noonan syndrome patients harboring causative variants inLZTR1are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. However, the underling disease mechanisms ofLZTR1missense variants driving the cardiac pathology are poorly understood. Hence, therapeutic options for Noonan syndrome patients are limited. In this study, we investigated the mechanistic consequences of a novel homozygous causative variantLZTR1L580Pby using patient-specific and CRISPR/Cas9-corrected iPSC-cardiomyocytes. Molecular, cellular, and functional phenotyping in combination within silicoprediction of protein complexes uncovered a uniqueLZTR1L580P-specific disease mechanism provoking the cardiac hypertrophy. The homozygous variant was predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymer chains. The altered polymerization resulted in dysfunction of the LZTR1-cullin 3 ubiquitin ligase complexes and subsequently, in accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data showed that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via the autophagosome, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent proteasomal pathways. Importantly, uni-or biallelic genetic correction of theLZTR1L580Pmissense variant rescued the molecular and cellular disease-associated phenotype, providing proof-of-concept for CRISPR-based gene therapies.
The potato resistance protein Rx1 multimerizes upon activation by the Coat Protein of PVX
Authors: Knip Marijn , Latul Emy , Takken Frank LW
Published: January 2023

Nucleotide-binding Leucine Rich repeat-type immune receptors (NLRs) are intracellular proteins that sense the presence of pathogen-derived elicitors and subsequently trigger an immune response. NLR proteins have to be strictly regulated as immune responses typically result in death of affected host cells. Regulation mechanisms of NLR activation are well studied, however steps immediately following NLR activation are largely unexplained. Multimerization of NLRs is thought to be involved, although currently no unambiguous paradigm regarding the dynamics of this process exists. Some NLRs form high-molecular weight complexes before activation, others exclusively after activation, or, like Rx1, none could be detected. We investigated NLR complex formation in transgenicN. benthamianastably expressing the potato Rx1 protein from its native promoter. Activation of the Rx1-resistance response was synchronized by dexamethasone-controlled expression of its elicitor; the Potato Virus X Coat Protein. Rx1 self-associates upon activation: Rx1 homomers are absent before dexamethasone application, a complex could be detected 1 hour after application, but surprisingly is again absent after 2 hours or later. These results show that self-association of NLR proteins upon activation can be transient, explaining the difficulties of detecting them during the normal, non-synchronized infection process as this typically involves few affected cells at any time.
Targeted gene deletion withSpCas9 and multiple guide RNAs inArabidopsis thaliana: four are better than two
Authors: Ordon Jana , Kiel Niklas , Becker Dieter , Kretschmer Carola , Schulze-Lefert Paul , Stuttmann Johannes
Published: January 2023

Background

In plant genome editing, RNA-guided nucleases such as Cas9 fromStreptococcus pyogenes(SpCas9) predominantly induce small insertions or deletions at target sites. This can be used for inactivation of protein-coding genes by frame shift mutations. However, in some cases, it may be advantageous to delete larger chromosomal segments. This is achieved by simultaneously inducing double strand breaks upstream and downstream of the fragment to be deleted. Experimental approaches for deletion induction have not been systematically evaluated.

Results

We designed three pairs of guide RNAs for deletion of the ArabidopsisWRKY30locus (~2.2 kb). We tested how the combination of guide RNA pairs and co-expression of the exonuclease TREX2 affect the frequency ofwrky30deletions in editing experiments. Our data demonstrate that compared to one pair of guide RNAs, two pairs increase the frequency of chromosomal deletions. The exonuclease TREX2 enhanced mutation frequency at individual target sites and shifted the mutation profile towards larger deletions. However, TREX2 did not elevate the frequency of chromosomal deletions.

Conclusions

Multiplex editing with at least two pairs of guide RNAs (four guide RNAs in total) elevates the frequency of chromosomal deletions, and thus simplifies the selection of corresponding mutants. Co-expression of the TREX2 exonuclease can be used as a general strategy to increase editing efficiency in Arabidopsis without obvious negative effects.
Application of the analytical hierarchy process for planning the rehabilitation of water distribution networks
Authors: Hassoun Nedjar Nizar , Djebbar Yassine , Djemili Lakhdar
Published: January 2023

Purpose

This study aims to develop a decision support tool to improve planning for the rehabilitation of water distribution networks (WDN) using the analytical hierarchy process (AHP) method and the urgency level score.

Design/methodology/approach

In this paper the AHP method was used to outclass the indicators having a strong influence on the deterioration of the pipes and the score of the level of urgency is calculated to establish the rehabilitation program (short, medium and long term). The proposed model was tested for the case of the city of Souk-Ahras in Algeria.

Findings

Based on the judgments of twenty-four experts, the relative weights of the three physical, operational and environmental criteria of the pipeline were calculated and found to be equal to 35.40%, 55.60% and 9.00%, respectively. The two indicators, number of failures and pressure, were found to have the highest overall weights. The results of this article can be used to improve decision-making in WDN rehabilitation planning in Algeria.

Research limitations/implications

The main objective of water companies is to provide citizens with good quality drinking water in sufficient quantity. However, over time, WDN age, degrade and deteriorate. This degradation leads to a drop in the performance through the degradation of water quality and an increase in loss rates. WDN rehabilitation is one of the most widely adopted solutions to address these drawbacks.

Originality/value

Application of a hybrid method (AHP- Level of Emergency) for the planning of the rehabilitation of WDN in Algeria.
Individual change agents for corporate sustainability transformation: a systematic literature review
Authors: Buhr Maike , Harms Dorli , Schaltegger Stefan
Published: January 2023

Purpose

Individual change agents for corporate sustainability can drive the transformation of organizations and foster sustainable development. Current research literature is growing and is published in a wide variety of journals. This systematic literature review provides an overview and synthesis of different understandings of individual change agents for corporate sustainability transformation. It identifies gaps and puts forward propositions to contribute to theoretical development in the field.

Design/methodology/approach

This paper conducts a systematic literature review and thematic content analysis of individual agency in light of corporate sustainability transformation.

Findings

The analysis identifies five research streams, three key dimensions of individual change agency for sustainability (beliefs, actions and competencies) and presents levels of individual agency for transformation. An integrated definition of change agents for sustainability is proposed.

Research limitations/implications

The review concludes with implications to support individuals in fostering sustainability transformations of organizations, markets and societies. The synthesis and propositions help in identifying which dimensions are already and could in future be addressed by individual change agents. While acknowledging the usual limitations of literature reviews, this paper can inspire future empirical research on the effectiveness of individual change agents for sustainability.

Originality/value

By synthesizing different understandings in the literature of individual change agents for sustainability, this article contributes to the theoretical development of individual agency in the areas of understandings, research streams, dimensions and perspectives. It also develops propositions on how individual change agency can effectively contribute to sustainability transformations at individual, organizational and systems levels.
An augmented multiphase rail launcher with a modular design: theoretical considerations and development
Authors: Zellmer Florian , Löffler Markus , Schneider Markus , Kreischer Christian
Published: January 2023

Purpose

The purpose of this paper is to investigate a novel approach toward electromagnetic launch.

Design/methodology/approach

The field of linear electromagnetic acceleration aims at accelerating macroscopic masses (up to several kg) to speeds in excess of 2 km/s. This can be achieved using accelerators of the railgun type. The innovation of this work lies in the use of multiphase current instead of the classically used quasi-direct current (DC). The approach taken is to work out in a first step the potential performance of such a configuration, for example, by showing that a constant propulsive force can be realized. Next, the necessary changes for the system setup were carefully analyzed. Both the accelerator and the power supply have to be considerably modified with regard to the classical approach.

Findings

Thorough analysis of the electromagnetic behavior of the launcher including nonlinear effects lead to an innovative system design which is considered to be the main finding of the work presented here. Moreover, a prototype was build. The preliminary experimental results obtained are in very good agreement with corresponding simulations validating the underlying modeling approach.

Research limitations/implications

For the purpose of this paper, power levels of only 450 kVA are considered. However, this research can be used to design more powerful devices in the future.

Originality/value

While DC powered railguns are modeled very well in a variety of papers, the use of multiphase alternating current is not very well discussed yet. It could be of value for launch scenarios, for which very high speeds are required such as the launch of micro satellites to space.
Compassion in the international business studies – prospects for future research
Authors: Jakobsen Michael , Worm Verner , Horak Sven
Published: January 2023

Purpose

This paper aims to introduce the concept of compassion to the field of international business studies. As international business activities continuously intensify and hence generate a work environment characterized by cultural heterogeneity and pluralism, the notion of compassion in a cross-cultural context can be regarded a key skill for employees in internationally operating firms to enable coping with potential cross-cultural conflicts.

Design/methodology/approach

In this narrative-oriented type of review, the authors discuss compassion in a cross-cultural context by drawing on the literature in the management and international business studies. By connecting prior research on compassion with the typical research interests in the IB domain, the authors identify and define potential future research foci for a research agenda centering on the role that cross-cultural compassion plays.

Findings

The authors argue that the conventional approach to learning about other national cultures, their value and norm systems, needs to be complemented by the acquisition of compassion skills. In todays culturally diverse business environment where employees increasingly work in virtual teams, cultural complexity is hardly manageable alone by developing expert knowledge about respective cultural contexts to prevent cross-cultural conflicts.

Originality/value

By drawing on extant research on compassion conducted in neighboring disciplines of the social sciences, the authors conceptualize compassion in the context of international business research. Because compassion in a cross-cultural context is new to international business research, this study suggests directions for future research consisting of four research streams to guide future research on compassion in a cross-cultural context in international business studies.
Managing the traceability system for food supply chain performance
Authors: Kafetzopoulos Dimitrios , Margariti Spiridoula , Stylios Chrysostomos , Arvaniti Eleni , Kafetzopoulos Panagiotis
Published: January 2023

Purpose

The objective of this study is to improve the food supply chain performance taking into consideration the fundamental concepts of traceability by combining the current frameworks, its principles, its implications and the emerging technologies.

Design/methodology/approach

A narrative literature review of already existing empirical research on traceability systems was conducted resulting in 862 relevant papers. Following a step-by-step sampling process, the authors ended up with 46 final samples for the literature review.

Findings

The main findings of this study include the various descriptions of the architecture of traceability systems, the different sources enabling this practice, the common desirable attributes, and the enabling technologies for the deployment and implementation of traceability systems. Moreover, several technological solutions are presented, which are currently available for traceability systems, and finally, opportunities for future research are provided.

Practical implications

It provides an insight, which could affect the implementation process of traceability in the food supply chain and consequently the effective management of a food traceability system (FTS). Managers will be able to create a traceability system, which meets users' requirements, thus enhancing the value of products and food companies.

Originality/value

This study contributes to the food supply chain and the traceability systems literature by creating a holistic picture of where something has been and where it should go. It is a starting point for each food company to design and manage its traceability system more effectively.
A systematic strategy of pallet identification and picking based on deep learning techniques
Authors: Li Yongyao , Ding Guanyu , Li Chao , Wang Sen , Zhao Qinglei , Song Qi
Published: January 2023

Purpose

This paper presents a comprehensive pallet-picking approach for forklift robots, comprising a pallet identification and localization algorithm (PILA) to detect and locate the pallet and a vehicle alignment algorithm (VAA) to align the vehicle fork arms with the targeted pallet.

Design/methodology/approach

Opposing vision-based methods or point cloud data strategies, we utilize a low-cost RGB-D camera, and thus PILA exploits both RGB and depth data to quickly and precisely recognize and localize the pallet. The developed method guarantees a high identification rate from RGB images and more precise 3D localization information than a depth camera. Additionally, a deep neural network (DNN) method is applied to detect and locate the pallet in the RGB images. Specifically, the point cloud data is correlated with the labeled region of interest (RoI) in the RGB images, and the pallet's front-face plane is extracted from the point cloud. Furthermore, PILA introduces a universal geometrical rule to identify the pallet's center as a “T-shape” without depending on specific pallet types. Finally, VAA is proposed to implement the vehicle approaching and pallet picking operations as a “proof-of-concept” to test PILA’s performance.

Findings

Experimentally, the orientation angle and centric location of the two kinds of pallets are investigated without any artificial marking. The results show that the pallet could be located with a three-dimensional localization accuracy of 1 cm and an angle resolution of 0.4 degrees at a distance of 3 m with the vehicle control algorithm.

Research limitations/implications

PILA’s performance is limited by the current depth camera’s range (< = 3 m), and this is expected to be improved by using a better depth measurement device in the future.

Originality/value

The results demonstrate that the pallets can be located with an accuracy of 1cm along the x, y, and z directions and affording an angular resolution of 0.4 degrees at a distance of 3m in 700ms.
Factors impeding the implementation of buildability assessment in building construction industry
Authors: Osuizugbo Innocent Chigozie
Published: January 2023

Purpose

Buildability assessment is an important tool used in improving buildability of building designs. Its practice has positive impact on construction project such as cost-saving, material waste reduction, labour-saving technologies, increase in efficiency, saving wasteful efforts and quality improvement as well as cost-effective methods of site construction and future maintenance. However, there are several factors hindering building construction industry to implement buildability assessment. In addition, there are few studies that described the factors impeding the implementation of buildability assessment in construction industry. This study aims to determine the factors impeding buildability assessment implementation in the Nigerian building construction industry

Design/methodology/approach

Quantitative research method was adopted for the study. Questionnaires were administered to purposively selected group of architects, engineers, builders and quantity surveyors. A total of 368 questionnaires were distributed among the sampled participants, out of which a total of 219 representing 60% were sufficiently filled and returned. Data elicited were analysed using inferential and descriptive statistics.

Findings

The results revealed that “poor co-ordination amongst different design disciplines”, “lack of buildability assessment awareness”, “design review pattern where construction personnel (builders) are invited to assess the building production information”, “unwillingness to invest extra money and effort during the early stage of project” and “designers value aesthetics and functionalities more than buildability in their designs” are the topmost five factors impeding buildability assessment implementation in the Nigerian construction industry.

Originality/value

This study highlights factors impeding the implementation of buildability assessment in construction industry. An understanding of these factors can help stakeholders in the construction industry facilitate the development of strategies required to mitigate the factors impeding buildability assessment implementation in the sector.