bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptional profiling in Arabidopsis root exposed to B toxicity at seedling stages
Authors: Yılmaz Hikmet , Kayıhan Ceyhun , Ünal Halis Batuhan , Yaprak Oğuzhan , Aksoy Emre 
Published: March 2023

AbstractCell-specific transcriptional responses to environmental stimuli are yet to be fully characterized in plants. In this study, we apply single-cell RNA sequencing toArabidopsis thalianaroots exposed to boron (B) toxicity to characterize the transcription map at cellular resolution and thus, to understand how B toxicity can alter gene expression and development at single cell resolution. Single-cell transcriptomes from protoplasts of more than 2750Arabidopsis thalianaroot cells were obtained. Plotting the single-cell transcriptomes via t-SNE projections yielded six major cell clusters including quiescent cells (QC), endodermis, cortex, columella, trichoblast (root-hair), and root cap. The maximum number of most significantly upregulated genes were determined in columella under 1 mM B and in endodermis under 2 mM B condition. Additionally, the maximum number of most significantly upregulated genes under 3 mM B and 5 mM B conditions was determined in the root cap, implying a critical role against severe B toxicity conditions. We also showed that these upregulated genes are highly correlated with “glutathione metabolism” in columella and “carbon metabolism” in root cap. Taken together, for the first time in the literature, our study provides a gene expression map at single-cell resolution and describes the extent of heterogeneity at the molecular level among populations of different cell types in Arabidopsis root under B toxicity conditions.
A genotype-phenotype taxonomy of hypertrophic cardiomyopathy
Authors: Curran Lara , de Marvao Antonio , Inglese Paolo , McGurk Kathryn A , Schiratti Pierre-Raphaël , Clement Adam , Zheng Sean L , Li Surui , Pua Chee Jian , Shah Mit , Jafari Mina , Theotokis Pantazis , Buchan Rachel J , Jurgens Sean J , Raphael Claire E , Baksi Arun John , Pantazis Antonis , Halliday Brian P , Pennell Dudley J , Bai Wenjia , Chin Calvin W L , Tadros Rafik , Bezzina Connie R , Watkins Hugh , Cook Stuart A , Prasad Sanjay K , Ware James S , O’Regan Declan P 
Published: March 2023

AbstractBackgroundHypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes but there is no systematic framework for classifying morphology or assessing associated risks. Here we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.MethodsWe enrolled 436 HCM patients (median age 60 years; 28.8% women) with clinical, genetic and imaging data. An independent cohort of 60 HCM patients from Singapore (median age 59 years; 11% women) and a reference population from UK Biobank (n = 16,691, mean age 55 years; 52.5% women) were also recruited. We used machine learning to analyse the three-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.ResultsCarriers of pathogenic or likely pathogenic variants for HCM (P/LP) variants had lower left ventricular mass, but greater basal septal hypertrophy, with reduced lifespan (mean follow-up 9.9 years) compared to genotype negative individuals (hazard ratio: 2.66; 95% confidence interval [CI]: 1.42-4.96;P< 0.002). Four main phenotypic branches were identified using unsupervised learning of three-dimensional shape: 1) non-sarcomeric hypertrophy with co-existing hypertension; 2) diffuse and basal asymmetric hypertrophy associated with outflow tract obstruction; 3) isolated basal hypertrophy; 4) milder non-obstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for P/LP variants: 2.18 [95% CI: 1.93-2.28,P= 0.0001]). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalisable to an independent cohort (trustworthinessM1: 0.86-0.88).ConclusionsWe report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.
Protocol of a Study to Benchmark Occupational Health and Safety in Japan: W2S-Ohpm Study
Authors: Nagata Tomohisa , Odagami Kiminori , Nagata Masako , Adi Nuri Purwito , Mori Koji 
Published: March 2023

AbstractWe aim to conduct a prospective cohort study to benchmark occupational health and safety in Japan. Here, we describe the detailed protocol for the baseline survey based on the Checklist for Reporting Results of Internet E-Surveys. We conducted the baseline survey for the prospective cohort study in 2022. Our target population was workers in Japan aged 20 years or older, who we sampled to be representative of the Japanese workforce, stratified by sex, age, and region. Among 59,272 registered monitors who answered the initial screening questions, 29,997 completed the survey. After excluding 2,304 invalid responses, we used 27,693 valid participants in our final analysis. The number and mean age of men were 15,201 (55%) and 46 years; those of women were 12,492 (45%) and 45 years. With respect to sex, age, and regional composition, our sampling was representative of Japan’s working population. Our sampling for employment status and industry yielded almost the same proportions as a government-led representative sampling of workers in Japan.
Temporal effects of sugar intake on fly local search and honey bee dance behaviour
Authors: Shakeel Manal , Brockmann Axel 
Published: March 2023

AbstractHoney bees communicate navigational information of profitable food to nestmates via dance, a small scale walking pattern. Hungry flies and honey bee foragers initiate a sugar-elicited local search that involves path integration and show similarities with dance behaviour. Using a comparative approach, we explored the temporal dynamics of initiation of local search and dance in flies and honey bees, respectively. Passive displacement experiments showed that feeding and initiation of search can be spatially dissociated in both species. Sugar intake increased the probability to initiate a search but onset of walking starts the path integration system guiding the search. When prevented from walking, the motivation to begin a path integration-based search was sustained for 3 min after sugar intake in flies and bees. In flies, the behavioural parameters of search were significantly reduced for 3 min but were higher than flies that were given no sugar stimulus, indicating some degree of meander. These results suggest that sugar elicits two independent behavioural responses: path integration and increased turning, and initiation and duration of path integration system is temporally more restricted. Honey bee dance experiments demonstrated that the motivation of foragers to initiate dance was sustained for 15 min, whereas the number of circuits declined after 3 min. Based on our findings, we propose that the food-intake during foraging has the capability to activate the path integration system in flies and honey bees, and this interaction might have been elaborated during evolution to guide the walking pattern of the honey bee dance.
Sinorhizobium melilotiFcrX coordinates cell cycle and division during free-living growth and symbiosis
Authors: Dendene Sara , Xue Shuanghong , Nicoud Quentin , Valette Odile , Frascella Angela , Bonnardel Anna , Le Bars Romain , Bourge Mickaël , Mergaert Peter , Brilli Matteo , Alunni Benoît , Biondi Emanuele G. 
Published: March 2023

ABSTRACTSinorhizobium melilotiis a soil bacterium that establishes a symbiosis within root nodules of legumes (Medicago sativa, for example) where it fixes atmospheric nitrogen into ammonia and obtains in return carbon sources and other nutrients. In this symbiosis,S. melilotiundergoes a drastic cellular change leading to a terminal differentiated form (called bacteroid) characterized by genome endoreduplication, increase of cell size and high membrane permeability. The bacterial cell cycle (mis)regulation is at the heart of this differentiation process. In free-living cells, the master regulator CtrA ensures the progression of cell cycle by activating cell division (controlled by the tubulin-like protein FtsZ) and simultaneously inhibiting supernumerary DNA replication, while on the other hand the downregulation of CtrA and FtsZ is essential for bacteroid differentiation during symbiosis, preventing endosymbiont division and permitting genome endoreduplication. Little is known inS. melilotiabout regulators of CtrA and FtsZ, as well as the processes that control bacteroid development. Here, we combine cell biology, biochemistry and bacterial genetics approaches to understand the function(s) of FcrX, a new factor that controls both CtrA and FtsZ, in free-living growth and in symbiosis. Depletion of the essential genefcrXled to abnormally high levels of FtsZ and CtrA and minicell formation. Using multiple complementary techniques, we showed that FcrX is able to interact physically with FtsZ and CtrA. Moreover, its transcription is controlled by CtrA itself and displays an oscillatory pattern in the cell cycle. We further showed that, despite a weak homology with FliJ-like proteins, only FcrX proteins from closely-related species are able to complementS. meliloti fcrXfunction. Finally, deregulation of FcrX showed abnormal symbiotic behaviors in plants suggesting a putative role of this factor during bacteroid differentiation. In conclusion, FcrX is the first known cell cycle regulator that acts directly on both, CtrA and FtsZ, thereby controlling cell cycle, division and symbiotic differentiation.
First crystal structure of double knotted protein TrmD-Tm1570 – inside from degradation perspective
Authors: da Silva Fernando Bruno , Lewandowska Iwona , Kluza Anna , Niewieczerzal Szymon , Augustyniak Rafał , Sulkowska Joanna I. 
Published: March 2023

AbstractHerein, we present the first crystal structure of a double knotted protein TrmD-Tm1570 fromCalditerrivibrio nitroreducens, as well the X-ray structure of each sub-domain. The protein consists of two domains TrmD and Tm1570, each embedding a single trefoil knot, which can function on their own. TrmD-Tm1570 forms a compact homodimeric complex. This protein represents one of 296 possible doubly knotted proteins from SPOUT family. Based on TrmD-Tm1570 fromCalditerrivibrio nitroreducenswe show that a double knotted protein can be fully degraded by the ClpXP degradation system, as well as its individual domains. We used numerical simulations to explain the difference in the speed of degradation. The derived kinetic parameters for the degradation process are comparable to the experimental data found for unknotted polypeptide chains.
The maizePLASTID TERMINAL OXIDASE(PTOX) gene controls the carotenoid content of kernels
Authors: Nie Yongxin , Wang Hui , Zhang Guan , Ding Haiping , Han Beibei , Liu Lei , Shi Jian , Du Jiyuan , Li Xiaohu , Li Xinzheng , Zhao Yajie , Zhang Xiaocong , Liu Changlin , Weng Jianfeng , Li Xinhai , Zhang Xiansheng , Zhao Xiangyu , Pan Guangtang , Jackson David , Wu Qingyu , Zhang Zhiming 
Published: March 2023

SUMMARYCarotenoids perform a broad range of important functions in humans; therefore, carotenoid biofortification of maize (Zea maysL.), one of the most highly produced cereal crops worldwide, would have a global impact on human health.PLASTID TERMINAL OXIDASE(PTOX) genes play an important role in carotenoid metabolism; however, the possible function ofPTOXin carotenoid biosynthesis in maize has not yet been explored. In this study, we identified the maizePTOXgeneZmPTOX1by forward genetic screening.While most higher plant species possess a single copy of thePTOXgene, maize carries two tandemly duplicated copies ofZmPTOX. Characterization ofZmptox1mutants revealed that disrupting one copy ofZmPTOX1was enough to impair carotenoid biosynthesis, indicating thatZmPTOX1is essential for carotenoid biosynthesis in maize kernels. Remarkably, overexpression ofZmPTOX1significantly improved the content of carotenoids, especially β-carotene (provitamin A), which was increased by ~3-fold, in maize kernels.Overall, our study shows thatZmPTOX1plays a crucial role in carotenoid biosynthesis in maize kernels and suggests that fine-tuning the expression of this gene could improve the nutritional value of cereal grains.
Distilling identifiable and interpretable dynamic models from biological data
Authors: Massonis Gemma , Villaverde Alejandro F. , Banga Julio R. 
Published: March 2023

AbstractMechanistic dynamical models allow us to study the behavior of complex biological systems. They can provide an objective and quantitative understanding that would be difficult to achieve through other means. However, the systematic development of these models is a non-trivial exercise and an open problem in computational biology. Currently, many research efforts are focused on model discovery, i.e. automating the development of interpretable models from data. One of the main frameworks is sparse regression, where the sparse identification of nonlinear dynamics (SINDy) algorithm and its variants have enjoyed great success. SINDy-PI is an extension which allows the discovery of rational nonlinear terms, thus enabling the identification of kinetic functions common in biochemical networks, such as Michaelis-Menten. SINDy-PI also pays special attention to the recovery of parsimonious models (Occam’s razor). Here we focus on biological models composed of sets of deterministic nonlinear ordinary differential equations. We present a methodology that, combined with SINDy-PI, allows the automatic discovery of structurally identifiable and observable models which are also mechanistically interpretable. The lack of structural identifiability and observability makes it impossible to uniquely infer parameter and state variables, which can compromise the usefulness of a model by distorting its mechanistic significance and hampering its ability to produce biological insights. We illustrate the performance of our method with six case studies. We find that, despite enforcing sparsity, SINDy-PI sometimes yields models that are unidentifiable. In these cases we show how our method transforms their equations in order to obtain a structurally identifiable and observable model which is also interpretable.Author summaryDynamical models provide a quantitative understanding of complex biological systems. Since their development is far from trivial, in recent years many research efforts focus on obtaining these models automatically from data. One of the most effective approaches is based on implicit sparse regression. This technique is able to infer biochemical networks with kinetic functions containing rational nonlinear terms. However, as we show here, one limitation is that it may yield models that are unidentifiable. These features may lead to inaccurate mechanistic interpretations and wrong biological insights. To overcome this limitation, we propose an integrated methodology that applies additional procedures in order to ensure that the discovered models are structurally identifiable, observable, and interpretable. We demonstrate our method with six challenging case studies of increasing model complexity.
A single base pair duplication inSLC33A1gene causes fetal losses and neonatal lethality in Manech Tête Rousse dairy sheep
Authors: Ben Braiek Maxime , Szymczak Soline , André Céline , Bardou Philippe , Fidelle Francis , Granado-Tajada Itsasne , Plisson-Petit Florence , Sarry Julien , Woloszyn Florent , Moreno-Romieux Carole , Fabre Stéphane 
Published: March 2023

AbstractRecently, we evidenced that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) was likely to harbor a recessive lethal variant in ovine. In the present study, we fine mapped this region by analyzing the whole genome sequence of five MTRDHH2 heterozygous carriers compared to 95 sequences of non-carrier animals from MTR and others ovine breeds. We successfully identified a single base pair duplication in theSLC33A1gene, resulting in a frameshift leading to a premature stop codon (p.Arg246Alafs*3). SLC33A1 acts as a transmembrane transporter of acetyl-Coenzyme A, essential for cellular metabolism. In order to assess for the lethal phenotype in homozygous MTR sheep, we generated at-risk matings by artificial insemination (AI) between rams and ewes heterozygous for theSLC33A1variant namedSLC33A1_dupG. Gestation status was checked 15 days post-AI by a molecular test from blood expression of the interferon Tau-stimulatedMX1gene, and by ultrasonography performed between 45 days and 60 days post-AI. Based on ultrasonography, the AI success was reduced by 12% compared to safe matings suggesting embryonic/fetal losses further confirmed by the molecular test based onMX1differential expression. Forty-nine lambs were born from at-risk matings with a mortality rate of 34.7% observed before weaning. HomozygousSLC33A1_dupG lambs contributed to 47% of this mortality occurring mainly in the first five days after lambing with no obvious clinical signs. Thus, an appropriate management ofSLC33A1_dupG (allele frequency of 0.04) in the MTR selection scheme should increase the overall fertility and lamb survival.
Non-invasive vagus nerve stimulation and the motivation to work for rewards: a replication
Authors: Lucchi Federica , Lloyd Beth , Nieuwenhuis Sander 
Published: March 2023

AbstractBackgroundThe vagus nerve is thought to be involved in the allostatic regulation of motivation and energy metabolism via gut-brain interactions. A recent study by Neuser and colleagues [1] provided novel evidence for this process in humans, by reporting a positive effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the invigoration of reward-seeking behaviors, especially for food rewards.ObjectiveWe conducted an independent direct replication of Neuser et al. [1], to assess the robustness of their findings.MethodsFollowing the original study, we used a single-blind, sham-controlled, randomized cross-over design. We applied left-sided taVNS in healthy human volunteers (n=40), while they performed an effort allocation task in which they had to work for monetary and food rewards. The replication study was purely confirmatory in that it strictly followed the analysis plans and scripts used by Neuser et al. [1].ResultsAlthough, in line with Neuser et al. [1], we found strong effects of task variables on effort invigoration and effort maintenance, we failed to replicate their key finding: taVNS did not increase the strength of invigoration (p= .62); the data were five times more likely (BF10= 0.19) under the null hypothesis. We also found substantial evidence against an effect of taVNS on effort maintenance (p= 0.50; BF10= 0.20).ConclusionsOur results provide evidence against the idea that taVNS boosts the motivational drive to work for rewards. Our study also highlights the need for direct replications of influential taVNS studies.
Novel exported bifunctional fusion enzymes with chorismate mutase and cyclohexadienyl dehydratase activity: shikimate pathway enzymes teamed up in no man’s land
Authors: Stocker Christian , Khatanbaatar Tamjidmaa , Würth-Roderer Kathrin , Cordara Gabriele , Krengel Ute , Kast Peter 
Published: March 2023

AbstractChorismate mutase (CM) and cyclohexadienyl dehydratase (CDT) catalyze two subsequent reactions in the intracellular biosynthesis of phenylalanine. Surprisingly, exported CMs and CDTs exist in bacterial pathogens. Here, we report the discovery of novel and extremely rare exported bifunctional fusion enzymes, consisting of fused CM and CDT domains. Such enzymes were found in only nine bacterial species belonging to non-pathogenic γ- or β-proteobacteria. In γ-proteobacterial fusion enzymes, the CM domain is N-terminal to the CDT domain, whereas in β-proteobacteria the order is inversed. The CM domains share 15-20% sequence identity with the AroQγclass CM holotype ofMycobacterium tuberculosis(*MtCM), and the CDT domains 40-60% identity with the exported monofunctional enzyme ofPseudomonas aeruginosa(PheC).In vitrokinetics revealed aKm<7 µM, much lower than for *MtCM, whereas kinetic parameters are similar for CDT domains and PheC. There is no feedback inhibition of CM or CDT by the pathway’s end product Phe, and no catalytic benefit of the domain fusion compared to engineered single-domain constructs. The fusion enzymes ofAequoribacter fuscus,Janthinobacteriumsp. HH01, andDuganella sacchariwere crystallized and their structures refined to 1.6, 1.7, and 2.4 Å resolution, respectively. Neither the crystal structures nor size-exclusion chromatography show evidence for substrate channeling or higher oligomeric structure that could account for cooperation of CM and CDT active sites. The genetic neighborhood with genes encoding transporter and substrate binding proteins suggests that these exported bifunctional fusion enzymes may participate in signaling systems rather than in the biosynthesis of Phe.
Frequency-coded patterns of sympathetic vasomotor activity are differentially evoked by the paraventricular nucleus of the hypothalamus in the Goldblatt hypertension model
Authors: Faber Jean , Milanez Maycon I. O. , Simões Cristiano S. , Campos Ruy R. 
Published: March 2023

ABSTRACTThe activation of specific brain areas involved in regulating the vasomotor sympathetic activity can lead to distinct effects in the postganglionic nerves in both physiological and pathological conditions, suggesting that the sympathetic vasomotor activity is differentially coded depending on the nerve outflow and the target organs. Previous studies investigating such patterns have mostly focused on the global energy of the signal. However, recent evidence has suggested that relevant information is coded in the power distribution along the frequency range. Disturbing the sympathoexcitatory vasomotor tone in the paraventricular nucleus of the hypothalamus (PVN) allows to investigate the sympathetic nerve activity in overloaded conditions in both hypertensive and control animals. By disinhibiting the PVN through the microinjection of bicuculline, an antagonist of γ-aminobutyric acid type A (GABAa) receptors, in the Goldblatt (2K1C) rat model of hypertension we addressed the territorially differential changes in the frequency parameters of the renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively). We also tested the effect of the systemic administration of losartan, an antagonist of the angiotensin II type 1 receptors (AT1), in the attenuation of the increased rSNA and sSNA in 2K1C rats, once these changes are reported to be dependent on the AT1 activation in the Goldblatt model. Our results revealed that each nerve activity presents its own electrophysiological pattern of frequency-coded rhythm in each group, in basal condition and after bicuculline microinjection, but with no significant differences regarding total power comparison among groups. Additionally, the 2K1C animals treated with losartan showed no decrease in the hypertensive response triggered by the GABAa antagonism when compared to the non-treated 2K1C group. However, their spectral patterns of sympathetic nerve activity were different from the other two groups, suggesting that the systemic blockade of AT1 receptors does not totally recover the basal levels of neither the autonomic symptoms nor the electrophysiological patterns in the Goldblatt model, but act on their spectral frequency distribution. These results suggest that the differential responses evoked by the PVN were preferentially coded in frequency of vasomotor sympathetic responses, indicating that the PVN distinctly modulated each rhythmic activity.Financial Support – FAPESP (2019/25295-0)