bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Look straight ahead” – A new test to diagnose spatial neglect by computed tomography
Authors: Marques Joel Coelho , Hanke Jens , Schell Caroline , Andres Frank , Karnath Hans-Otto 
Published: August 2022

AbstractSpatial neglect is the dominant behavioral disorder after right hemisphere brain lesions. Reliable diagnosis by formal neuropsychological testing is often achieved only later during hospitalization, leading to delays in targeted therapies. We propose a way to diagnose spatial neglect right at admission. We measured the conjugated eye deviation (CED) on the initial computed tomography (CT) scans, in combination with the verbal instruction “Please look straight ahead” during the scan. The command was implemented in the scanner program and automatically played before a cranial CT started. This prospective study included a total 46 consecutive subjects (16 patients with first ever right brain damage and no spatial neglect, 12 patients with first ever right brain damage and spatial neglect, and 18 healthy controls). The right brain damaged groups were submitted to paper pencil tests to access the diagnosis of a spatial neglect after radiological confirmation of the brain damage during the initial phase of their hospitalisation. This procedure allowed us to define a cut-off value of 14.1 degrees of CED to the ipsilesional side to differentiate right hemispheric stroke patients with versus without spatial neglect with a confidence interval of 99%. This simple addition to a radiological routine procedure provides a new tool to help diagnose spatial neglect at the earliest stage possible and thus offers the possibility of providing patients with optimized rehabilitative therapy from a very early stage on.
Integration of biomarker polygenic risk score improves prediction of coronary heart disease in UK Biobank and FinnGen
Authors: Lin Jake , Mars Nina , Fu Yu , Ripatti Pietari , Kiiskinen Tuomo , FinnGen  , Tukiainen Taru , Ripatti Samuli , Pirinen Matti 
Published: August 2022

AbstractBackgroundIn addition to age and sex, also smoking history and levels of blood pressure, cholesterol, lipoproteins and inflammation are established biomarkers for coronary heart disease (CHD). As standard polygenic risk scores (PRS) have recently proven successful for CHD prediction, it remains of high interest to determine how a combined PRS of biomarkers (BioPRS) constructed from statistically relevant biomarkers can further improve genetic prediction of CHD.MethodsWe developed CHDBioPRS, which combines BioPRS with PRS of CHD, via regularized regression in UK Biobank (UKB) training data (n = 208,010). The resulting CHDBioPRS was tested on an independent UK Biobank subset (n = 25,765) and on the FinnGen study (n = 306,287).ResultsWe observed a consistent pattern across all data sets where BioPRS was clearly predictive of CHD and improved standard PRS for CHD when the two were combined. In UKB test data, CHDPRS had a hazard ratio (HR) of 1.78 (95% confidence interval 1.67-1.91, area under the curve (AUC) 0.808) and CHDBioPRS had a HR of 1.88 (1.75-2.01, AUC 0.811) per one standard deviation of PRS. In FinnGen data, HR of CHDPRS was 1.57 (1.55-1.60, AUC 0.752) and HR of CHDBioPRS was 1.60 (1.58-1.62, AUC 0.755). We observed larger effects of CHDBioPRS in subsets of early onset cases with HR of 2.07 (1.85-2.32, AUC 0.790) in UKB test data and of 2.10 (2.04-2.16, AUC 0.791) in FinnGen. Results were similar when stratified by sex.ConclusionsIntegration of biomarker based BioPRS improved on the standard PRS for CHD and the gain was largest with early onset CHD cases. These findings highlight the benefit of enriching polygenic risk prediction of CHD with the genetics of associated biomarkers.
Helicobacter pylori vacuolating cytotoxin A exploits human endosomes for intracellular activation
Authors: Palframan Samuel L , Mahmud Md. Toslim , Tan Kher Shing , Grinter Rhys , Xin Vicky , Dunstan Rhys A , Micati Diana , Kerr Genevieve , McMurrick Paul J , Smith Andrew , Abud Helen , Nguyen Thanh Ngoc , Lazarou Michael , Kleifeld Oded , Lithgow Trevor , Cover Timothy L , Gabriel Kipros , Gorrell Rebecca J , Kwok Terry 
Published: August 2022

AbstractHelicobacter pylori infection is the main cause of gastric cancer. Vacuolating cytotoxin A (VacA) is a H. pylori pore-forming toxin and a key determinant of gastric cancer risk. VacA is secreted as an 88-kDa polypeptide (p88) that upon interaction with host cells induces cytotoxic effects, including cell vacuolation and mitochondrial dysfunction. These effects are currently believed to be due to VacA p88 accumulating inside host cells and forming oligomeric anion-specific channels in membranes of intracellular compartments. However, the molecular nature of intracellular VacA channels in host cells remains undefined. Here we show that VacA p88 does not accumulate inside human epithelial cells, but instead is rapidly processed in endosomes into smaller p31/p28 and p37 products in a manner that precedes VacA-induced vacuolation. VacA processing requires endosomal acidification and concerted cleavage by multiple endo-lysosomal proteases including cathepsins. In situ structural mapping reveals that upon processing, the toxin’s central hydrophilic linker and globular C-terminus are excised, whereas oligomerization determinants are retained. Congruently, the processed products are constituents of a high-molecular-weight complex inside the host cell ─ which we propose is the intracellular, mature and active VacA pore. These findings suggest that VacA exploits human endosomes for proteolytic processing and intracellular activation.Significance StatementHelicobacter pylori is a cancer-causing bacterium that infects the stomach of billions of people worldwide. Vacuolating cytotoxin A (VacA) is an important H. pylori virulence factor and its activity directly correlates with gastric carcinogenesis. Yet despite decades of intense research, the mechanisms underlying VacA activity in human cells remain incompletely understood. Here, we present evidence suggesting that VacA is activated inside human cells by multi-step proteolytic processing involving endo-lysosomal proteases including cathepsins. We also track and identify the functional processed VacA isoforms in host cells. These results revolutionize our understanding of the mechanism of VacA activation in human cells, whilst expanding our knowledge of the diversity of microbial virulence factors that exploit human endo-lysosomes for pathogenesis.
Integrating carbon stocks and wildlife connectivity for nature-based climate solutions
Authors: O’Brien Paul , Gunn John S. , Clark Alison , Gleeson Jenny , Pither Richard , Bowman Jeff 
Published: August 2022

AbstractActions to protect against biodiversity loss and climate change will require a framework that addresses synergies between these interrelated issues. In this study we present methods for identifying areas important for the implementation of nature-based climate solutions and biodiversity conservation by intersecting high resolution spatial data for carbon storage and terrestrial connectivity. We explored the spatial congruence of carbon and connectivity in Ontario, Canada and examined effectiveness of current protected areas coverage. We found a weak positive relationship between carbon stocks and terrestrial connectivity; however, our maps revealed large hotspots, with high values of both indices, throughout the boreal forest and northern peatlands and smaller, isolated hotspots in the settled landscapes of the south. Location of hotspots varied depending on whether we considered forest or soil carbon. Further, our results show that current protected and conserved areas in Ontario only cover 13% of landscapes with the highest values for both carbon storage and connectivity. Protection or restoration of areas that maximize the co-benefits of carbon storage and connectivity would make significant contributions towards ambitious national targets to reduce greenhouse gas emissions and conserve biodiversity.
CIPK-B is essential for salt stress signalling in Marchantia polymorpha
Authors: Tansley Connor , Houghton James , Rose Althea M. E. , Witek Bartosz , Payet Rocky D. , Wu Taoyang , Miller J. Benjamin 
Published: August 2022

SUMMARYCalcium signalling is central to many plant processes, with families of calcium decoder proteins having expanded across the green lineage and redundancy existing between decoders. The liverwort Marchantia polymorpha has fast become a new model plant, but it is unclear what calcium decoders exist in this species.We have performed phylogenetic analyses to identify the Calcineurin B-Like (CBL) and CBL-Interacting Protein Kinase (CIPK) network of M. polymorpha. We analysed CBL-CIPK expression during salt stress, and determined protein-protein interactions using yeast two-hybrid and bimolecular fluorescence complementation. We also created genetic knockouts using CRISPR/Cas9.We confirm that M. polymorpha has two CIPKs and three CBLs. Both CIPKs and only one CBL show salt-responsive transcriptional changes. All M. polymorpha CBL-CIPKs interact with each other in planta. Knocking out CIPK-B causes increased sensitivity to salt suggesting that this CIPK is involved in salt signalling.We have identified CBL-CIPKs that form part of a salt tolerance pathway in M. polymorpha. Phylogeny and interaction studies imply that these CBL-CIPKs form an evolutionarily conserved Salt Overly Sensitive (SOS) pathway. Hence, salt responses may be some of the early functions of CBL-CIPK networks and increased abiotic stress tolerance required for land plant emergence.
Structural and functional insights into the type III-E CRISPR-Cas immunity
Authors: Liu Xi , Zhang Laixing , Wang Hao , Xiu Yu , Huang Ling , Gao Zhengyu , Li Ningning , Li Feixue , Xiong Weijia , Gao Teng , Zhang Yi , Yang Maojun , Feng Yue 
Published: August 2022

SummaryThe type III-E CRISPR-Cas system comprises a Cas effector (gRAMP), a TPR-CHAT and several ancillary proteins. However, both the structural features of gRAMP and the immunity mechanism remain unknown for this system. Here, we report a series of structures of gRAMP-crRNA, either its alone or in complex with target RNA or TPR-CHAT (called Craspase), and Craspase complexed with cognate (CTR) or non-cognate target RNA (NTR). Importantly, the 3’ anti-tag region of NTR and CTR bind at two distinct channels in the Craspase, and CTR with a non-complementary 3’ anti-tag induces a marked conformational change of the TPR-CHAT, which allosterically activates its protease activity to cleave an ancillary protein Csx30. This cleavage then triggers an abortive infection as the antiviral strategy of the type III-E system. Together, our study provides crucial insights into both the catalytic mechanism of the gRAMP and the immunity mechanism of the type III-E CRISPR-Cas system.
Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20
Authors: Preiss Nicholas K. , Kamal Yasmin , Williams Owen M. , Li Chenyang , Kolling Fred W. , Trask Heidi W. , Usherwood Young-Kwang , Cheng Chao , Frost Hildreth R. , Usherwood Edward J. 
Published: August 2022

AbstractMembers of the BTB-ZF transcription factor family regulate the immune system. Our lab identified that family member Zbtb20 contributes to the differentiation, recall responses and metabolism of CD8 T cells. Here, we report a characterization of the transcriptional and epigenetic signatures controlled by Zbtb20 at single-cell resolution during the effector and memory phases of the CD8 T cell response. Without Zbtb20, transcriptional programs associated with memory CD8 T cell formation were upregulated throughout the CD8 T response. A signature of open chromatin was associated with genes controlling T cell activation, consistent with the known impact on differentiation. Additionally, memory CD8 T cells lacking Zbtb20 were characterized by open chromatin regions with overrepresentation of AP-1 transcription factor motifs and elevated RNA- and protein-level expression of the corresponding AP-1 components. Finally, we describe motifs and genomic annotations from the DNA targets of Zbtb20 in CD8 T cells identified by CUT&RUN. Together, these data establish the transcriptional and epigenetic networks contributing to the control of CD8 T cell responses by Zbtb20.
resevol: an R package for spatially explicit models of pesticide resistance given evolving pest genomes
Authors: Duthie A. Bradley , Mangan Rosie , McKeon C. Rose , Tinsley Matthew C. , Bussière Luc F. 
Published: August 2022

AbstractThe evolution of pesticide resistance is a widespread problem with potentially severe consequences for global food security. We introduce the resevol R package, which simulates individual-based models of pests with evolving genomes that produce complex, polygenic, and covarying traits affecting pest life history and pesticide resistance. Simulations are modelled on a spatially-explicit and highly customisable landscape in which crop and pesticide application and rotation can vary, making the package a highly flexible tool for both general and tactical models of pest management and resistance evolution. We present the key features of the resevol package and demonstrate its use for a simple example simulating pests with two covarying traits. The resevol R package is open source under GNU Public License. All source code and documentation are available on GitHub.
Focal exocytosis of Syntaxin 3 and TRPML1 at pseudopodia of nascent phagosomes
Authors: Dabral Deepti , van Bogaart Geert 
Published: August 2022

AbstractMacrophages clear invading pathogens by phagocytosis. Phagocytosis is a complex mechanism involving the local expansion of the membrane, cytoskeletal remodeling, and the delivery of phagosomal proteins to the nascent phagosomes. However, the organelle trafficking events underlying this are largely unclear. Here, we show in human blood monocyte-derived macrophages that TRPML1, a calcium channel involved in the phagocytic process, is delivered to phagosomes in Syntaxin 3-positive vesicles. Syntaxin 3 is a SNARE protein previously shown to mediate the secretion of IL-6 by macrophages. Total Internal Reflection Microscopy (TIRF) revealed that Syntaxin 3 positive compartments carry TRPML1 to pseudopodia for focal exocytosis at the nascent phagosomes during E. coli uptake. Using siRNA knockdown, we show that both Syntaxin 3 and TRPML1 are required for E. coli uptake. Moreover, using TRPML1 agonists we show that increased TRPML1 activity leads to increased E. coli uptake, whereas calcium chelation decreased intracellular E. coli load. Understanding the membrane trafficking pathways is critical for understanding how macrophages clear invading pathogens.Key findingsSyntaxin 3 positive vesicles are delivered at the plasma membrane site of phagocytosis.Syntaxin 3-positive vesicles carry TRPML1 to pseudopodia.Bacterial phagocytosis correlates with Syntaxin 3 and TRPML1 expression levels.Bacterial phagocytosis depends on calcium flux through TRPML1.Syntaxin-3 vesicles carry the cytokine interleukin-6.
Biochemical analysis of anthocyanin and proanthocyanidin and their regulation in determining chickpea flower and seed coat colours
Authors: Pal Lalita , Dwivedi Vikas , Gupta Santosh Kumar , Saxena Samiksha , Pandey Ashutosh , Chattopadhyay Debasis 
Published: August 2022

AbstractFlower and seed coat colour are important agronomic traits in chickpea (Cicer arietinum L.). Cultivated chickpeas are of two types namely, desi (dark seeded, purple flower) and kabuli (light colour seeded, white flower). There has been limited information about the molecular mechanism underlying the colour variation of flower and seed coats in desi and kabuli chickpea. We profiled the anthocyanin and proanthocyanidin (PA) contents in chickpea flowers and seed coats. Tissue-specific silencing of two genes encoding a basic helix-loop-helix (CabHLH) protein and a tonoplast-localized multidrug and toxic compound extrusion (CaMATE1) transporter in a desi genotype resulted in the reduction in expressions of anthocyanin and PA biosynthetic genes and anthocyanin and PA contents in the flower and seed coat and produced flowers and seeds with kabuli characteristics. Transcriptional regulation of a subset of anthocyanin and PA biosynthetic genes by a natural CabHLH variant and transport assay of a natural CaMATE1 variant explained the association of these alleles with the kabuli phenotype. We carried out a detailed molecular characterization of these genes, and provided evidences that kabuli chickpea flower and seed colour phenotype can be derived by manipulation of single genes in a desi chickpea background.HighlightIn this study, we have defined the molecular link between flower and seed color in chickpea and identified CaMATE1 and CabHLH as the regulators of both the traits.
A highly polymorphic effector protein promotes fungal virulence through suppression of plant-associated Actinobacteria
Authors: Snelders Nick C. , Boshoven Jordi C. , Song Yin , Schmitz Natalie , Fiorin Gabriel L. , Rovenich Hanna , van den Berg Grardy C.M. , Torres David E. , Faino Luigi , Seidl Michael F. , Thomma Bart P.H.J. 
Published: August 2022

ABSTRACTPlant pathogens secrete effector proteins to support host colonization through a wide range of molecular mechanisms, while plant immune systems evolved receptors to recognize effectors or their activities to mount immune responses to halt pathogens. Importantly, plants do not act as single organisms, but rather as holobionts that actively shape their microbiota as a determinant of health, and may thus be targeted by pathogen effectors as such. The soil-borne fungal pathogen Verticillium dahliae was recently demonstrated to exploit the VdAve1 effector to manipulate the host microbiota to promote vascular wilt disease in absence of the corresponding immune receptor Ve1. We now identified a multiallelic V. dahliae gene displaying ~65% sequence similarity to VdAve1, named VdAve1-like (VdAve1L). Interestingly, VdAve1L shows extreme sequence variation, including alleles that encode dysfunctional proteins, indicative of selection pressure to overcome host recognition. We show that the orphan cell surface receptor Ve2, encoded at the Ve1 locus, does not recognize VdAve1L. Furthermore, we show that the full-length variant VdAve1L2 possesses antimicrobial activity, like VdAve1, yet with a divergent activity spectrum. Altogether, VdAve1L2 is exploited by V. dahliae to mediate tomato colonization through the direct suppression of antagonistic Actinobacteria in the host microbiota. Our findings open up strategies for more targeted biocontrol against microbial plant pathogens.
Evolutionary determinants of reproductive seasonality: a theoretical approach
Authors: Burtschell Lugdiwine , Dezeure Jules , Huchard Elise , Godelle Bernard 
Published: August 2022

AbstractReproductive seasonality is a major adaptation to seasonal cycles and varies substantially among organisms. This variation, which was long thought to reflect a simple latitudinal gradient, remains poorly understood for many species, in part due to a lacunary theoretical framework. Because seasonal cycles are increasingly disrupted by climate change, a better understanding of the ecology of reproductive seasonality could generate important insights on how climate change may affect biodiversity. The goal of this study was to investigate the drivers of evolutionary transitions towards reproductive seasonality using a realistic agent-based optimisation model simulating the life cycle of a female yellow baboon, who typically breeds year-round. Specifically, we tested the influence of three ecological traits (environmental seasonality, productivity and unpredictability) and three life-history traits (daily reproductive energy expenditure, reproductive cycle length and infant extrinsic mortality) on the intensity of reproductive seasonality. To do so, we simulated diverse reproductive phenology strategies (from non-seasonal to highly seasonal), assessed which were optimal and computed, for the set of optimal strategies, the intensity of reproductive seasonality. We then induced variation in each trait of interest and examined how it affected the intensity of reproductive seasonality. We found significant effects of all three environmental traits: high reproductive seasonality was favoured by high environmental seasonality, low environmental productivity and low unpredictability. It was further, and most strongly, favoured by high daily reproductive energy expenditure. In contrast, there was no significant effect of reproductive cycle length and infant extrinsic mortality. Our modelling approach successfully disentangled the effects of environmental seasonality, productivity and unpredictability on the intensity of reproductive seasonality, which likely all contribute to generate the well-known association between latitude and reproductive seasonality. Our results further highlight the critical importance of life history pace on the evolution of reproductive seasonality. Overall, this study contributes a powerful theoretical framework and modelling tool that may apply across the life-history space, as well as sheds new light on the emergence and maintenance of non-seasonal breeding in slow-living species, including humans.
Targeted genome editing in grape using multiple CRISPR-guided editing systems
Authors: Ren Chong , Lin Yanping , Li Huayang , Li Shaohua , Liang Zhenchang 
Published: August 2022

AbstractThe CRISPR/Cas9 system, together with newly developed CRISPR technologies such as CRISPR/LbCpf1 and base editors, have expanded the scope of targeted genome editing in plants. However, in grape, applications of these novel CRISPR-guided tools have not been reported. Here, we employed EGFP (enhanced green fluorescent protein) and RUBY to help to screen transformed grape cells based on fluorescence and red betalain and tested the activities of CRISPR/LbCpf1, CRISPR/xCas9 and cytidine base editor (CBE) in grape, respectively. The grape TMT1 (tonoplastic monosaccharide transporter1) and TMT2 genes were simultaneously edited by using LbCpf1, resulting in an efficiency of 16-48%. Furthermore, high temperature (34°C) could enhance editing efficiencies at most of the designed targets. The CRISPR/xCas9 could induce targeted mutagenesis at the target with NGG PAM, but the efficiencies were very low (< 1.9%). The targets with GAA and GAT PAMs that are reported in mammalian cells and rice were not recognized by xCas9 in our study. Moreover, successful C-to-T substitutions were achieved in GAI1 (gibberellin insensitive1) gene by using CBE. The editing efficiencies ranged from 2.4 to 15% at the two targets in GAI1 in grape cells. Analysis of independent embryos revealed a C-to-T efficiency of 12.5% at the first target of GAI1. Taken together, our results demonstrate the efficacy of these CRISPR-guided tools in grape and provide evidence for further application of these editing tools in this economically important species.