bluuebunny/crossref_metadata_2025 huggingface dataset:
Motor variability prior to learning is a poor predictor of the ability to adopt new movement solutions
Authors: Ranganathan Rajiv , Lin Marco , Carey Samuel , Lokesh Rakshith , Lee Mei-Hua , Krishnan Chandramouli
Published: October 2020

Many contexts in motor learning require a learner to change from an existing movement solution to a novel movement solution to perform the same task. Recent evidence has pointed to motor variability prior to learning as a potential marker for predicting individual differences in motor learning. However, it is not known if this variability is predictive of the ability to adopt a new movement solution for the same task. Here, we examined this question in the context of a redundant precision task requiring control of motor variability. Fifty young adults learned a precision task that involved throwing a virtual puck toward a target using both hands. Because the speed of the puck depended on the sum of speeds of both hands, this task could be achieved using multiple solutions. Participants initially performed a baseline task where there was no constraint on the movement solution, and then performed a novel task where they were constrained to adopt a specific movement solution requiring asymmetric left and right hand speeds. Results showed that participants were able to learn the new solution, and this change was associated with changes in both the amount and structure of variability. However, individual differences in baseline motor variability were only weakly correlated with initial and final task performance when using the new solution, with greater variability being associated with higher errors. We also found a strong specificity component – initial variability when using the new solution was highly correlated with final task performance with the new solution, but once again, higher variability was associated with greater errors. These results suggest that motor variability is not necessarily indicative of flexibility and highlight the need to consider the task context in determining the relation between motor variability and learning.
Protein hyperacylation links mitochondrial dysfunction with nuclear organization
Authors: Smestad John , McCauley Micah , Amato Matthew , Xiong Yuning , Liu Juan , Sin Yi-Cheng , Ellingson Jake , Chen Yue , Al Khazal Fatimah , Wilbanks Brandon , Lee Jeong-Heon , Ordog Tamas , Rouzina Ioulia , Williams Mark , Locasale Jason W. , Maher L. James
Published: October 2020

Cellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (∼102bp), topologically-associated domains (TADs; ∼105– 106bp), and chromatin compartments (106– 108bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.
A damaged-informed lung ventilator model for ventilator waveforms
Authors: Agrawal Deepak K. , Smith Bradford J. , Sottile Peter D. , Albers David J.
Published: October 2020

Motivated by desire to understand pulmonary physiology and pathophysiology, scientists have developed models of pulmonary physiology. However, pathophysiology and interactions between human lungs and ventilators, e.g., ventilator-induced lung injury (VILI), present problems for modeling efforts. Real-world injury is too complex for simple models to capture, and while complex models tend not to be estimable with clinical data, limiting both the clinical utility with existing approaches. To address this gap, we present a damaged-informed lung ventilator (DILV) model to model and quantify patient-ventilator interactions and lung health. This approach relies on systematically mathematizing the pathophysiologic knowledge clinicians use to interpret lung condition from ventilator waveform data. This is achieved by defining clinically relevant features in the ventilator waveform data that contain hypothesis-driven information about pulmonary physiology, patient-ventilator interaction, and ventilator settings. To capture these features, we develop a modelling framework where the model has enough flexibility to reproduce commonly observed variability in waveform data. We infer the model parameters with clinical (human) and laboratory (mouse) data. The DILV model can reproduce essential dynamics of differently damaged lungs for tightly controlled measurements in mice and uncontrolled human intensive care unit data in the absence and presence of respiratory effort. Estimated parameters correlate with known measures of lung physiology, including lung compliance. This method has the potential to translate laboratory physiology experiments to clinical applications, including pathways for high fidelity estimates of lung state and sources of VILI with an end goal of reducing the impact of VILI and acute respiratory distress syndrome.
MADS-box genes galore in wheat genome: phylogenomics, evolution and stress associated functions
Authors: Raza Qasim , Riaz Awais , Atif Rana Muhammad , Hussain Babar , Ali Zulfiqar , Budak Hikmet
Published: October 2020

MADS-box gene family members play multifarious roles in regulating the growth and development of crop plants and hold enormous promise for bolstering grain yield potential under changing global environments. Bread wheat (Triticum aestivumL.) is a key stable food crop around the globe. Until now, the available information concerning MADS-box genes in the wheat genome has been insufficient. However, a comprehensive genome-wide analysis identified 300 high confidence MADS-box genes from the latest publicly available reference genome of wheat. Comparative phylogenetic analyses withArabidopsisand rice MADS-box genes classified the wheat genes into 16 distinct subfamilies, without a singleFLOWERING LOCUS Chomolog present in the wheat genome. Gene duplications were mainly identified in subfamilies containing unbalanced homeologs, pointing towards a potential mechanism for gene family expansion. Moreover, a more recent evolutionary origin was inferred for M-type genes, as compared with MIKC-type genes, indicating their significance in understanding the evolutionary history of the wheat genome. We speculate that subfamily-specific distal telomeric duplications in unbalanced homeologs facilitate the rapid adaptation of wheat to changing environments. Furthermore, ourin-silicoexpression data strongly proposed MADS-box genes as active guardians of plants against pathogen insurgency and harsh environmental conditions. In conclusion, we provide an entire complement of MADS-box genes identified in the wheat genome that will accelerate functional genomics efforts and possibly facilitate bridging gaps between genotype-to-phenotype relationships through fine-tuning of agronomically important traits.
Epidemiological dynamics of bacteriocin competition and antibiotic resistance
Authors: Lehtinen Sonja , Croucher Nicholas J. , Blanquart François , Fraser Christophe
Published: October 2020

Bacteriocins, toxic peptides involved in the competition between bacterial strains, are extremely diverse. Previous work on bacteriocin dynamics has highlighted the role of non-transitive ‘rock-paper-scissors’ competition in maintaining the coexistence of different bacteriocin profiles. The focus to date has primarily been on bacteriocin interactions at the within-host scale. Yet, in species such asStreptococcus pneumoniaewith relatively short periods of colonisation and limited within-host diversity, ecological outcomes are also shaped by processes at the epidemiological (between-host) scale. Here, we first investigate bacteriocin dynamics and diversity in epidemiological models. We find that in these models, bacteriocin diversity is more readily maintained than in within-host models, and with more possible combinations of coexisting bacteriocin profiles. Indeed, maintenance of diversity in epidemiological models does not require rock-paper-scissors dynamics; it can also occur through a competition-colonisation trade-off. Second, we investigate the link between bacteriocin diversity and diversity at antibiotic resistance loci. Previous work has proposed that bacterial duration of colonisation modulates the fitness of antibiotic resistance. Due to their inhibitory effects, bacteriocins are a plausible candidate for playing a role in the duration of colonisation episodes. We extend the epidemiological model of bacteriocin dynamics to incorporate an antibiotic resistance locus and demonstrate that bacteriocin diversity can indeed maintain the coexistence of antibiotic sensitive and resistant strains.
Limited and strain-specific transcriptional and growth responses to acquisition of a multidrug resistance plasmid in genetically diverseEscherichia colilineages
Authors: Dunn Steven , Carrilero Laura , Brockhurst Michael , McNally Alan
Published: October 2020

Multi-drug resistant (MDR)Escherichia coliare a major global threat to human health, wherein multi-drug resistance is primarily spread by MDR plasmid acquisition. MDR plasmids are not widely distributed across the entireE. colispecies, but instead are concentrated in a small number of clones. Here, we test if diverseE. colistrains vary in their ability to acquire and maintain MDR plasmids, and if this relates to their transcriptional response following plasmid acquisition. We used strains from across the diversity ofE. coli,including the common MDR lineage ST131, and the IncF plasmid, pLL35, encoding multiple antibiotic resistance genes. Strains varied in their ability to acquire pLL35 by conjugation, but all were able to stably maintain the plasmid. The effects of pLL35 acquisition on cefotaxime resistance and growth also varied among strains, with growth responses ranging from a small decrease to a small increase in growth of the plasmid-carrier relative to the parental strain. Transcriptional responses to pLL35 acquisition were limited in scale and highly strain specific. We observed significant transcriptional responses at the operon or regulon level, possibly due to stress responses or interactions with resident MGEs. Subtle transcriptional responses consistent across all strains were observed affecting functions, such as anaerobic metabolism, previously shown to be under negative frequency dependent selection in MDRE. coli.Overall, there was no correlation between the magnitude of the transcriptional and growth responses across strains. Together these data suggest that fitness costs arising from transcriptional disruption are unlikely to act as a barrier to dissemination of this MDR plasmid inE. coli.

Importance

Plasmids play a key role in bacterial evolution by transferring niche adaptive functions between lineages, including driving the spread of antibiotic resistance genes. Fitness costs of plasmid acquisition arising from the disruption of cellular processes could limit the spread of multidrug resistance plasmids. However, the impacts of plasmid acquisition are typically measured in lab-adapted strains rather than in more ecologically relevant natural isolates. Using a clinical multidrug resistance plasmid and a diverse collection ofE. colistrains isolated from clinical infections and natural environments, we show that plasmid acquisition had only limited and highly strain-specific effects on bacterial growth and transcription. These findings suggest that fitness costs arising from transcriptional disruption are unlikely to act as a barrier to transmission of this plasmid in natural populations ofE. coli.
Synthetic model ecosystem of 12 cryopreservable microbial species allowing for a noninvasive approach
Authors: Hosoda Kazufumi , Seno Shigeto , Murakami Naomi , Matsuda Hideo , Osada Yutaka , Kamiura Rikuto , Kondoh Michio
Published: October 2020

Simultaneous understanding of both individual and ecosystem dynamics is crucial in an era marked by the degradation of ecosystem services. Herein, we present a high-throughput synthetic microcosm system comprising 12 functionally and phylogenetically diverse microbial species. These species are axenically culturable, cryopreservable, and can be measured noninvasively via microscopy, aided by machine learning. This system includes prokaryotic and eukaryotic producers and decomposers, and eukaryotic consumers to ensure functional redundancy. Our model system displayed both positive and negative interspecific interactions and higher-order interactions that surpassed the scope of any two-species interaction. Although complete species coexistence was not our primary objective, we identified several conditions under which at least one species from the producers, consumers, and decomposers groups, and one functionally redundant species, persisted for over six months. These conditions set the stage for detailed investigations in the future. Given its designability and experimental replicability, our model ecosystem offers a promising platform for deeper insights into both individual and ecosystem dynamics, including evolution and species interactions.
EEG alpha-theta dynamics during mind wandering in the context of breath focus meditation: an experience sampling approach with novice meditation practitioners
Authors: Rodriguez-Larios Julio , Alaerts Kaat
Published: October 2020

Meditation practice entails moments of distraction dominated by self-generated thoughts (i.e. mind wandering). Initial studies assessing the neural correlates of mind wandering in the context of meditation practice have identified an important role of theta (4-8 Hz) and alpha (8-14 Hz) neural oscillations. In this study, we use a probe-caught experience sampling paradigm to assess spectral changes in the theta-alpha frequency range during mind wandering in the context of breath focus meditation. Electroencephalography (EEG) was measured in 25 novice meditation practitioners during a breath focus task in which they were repeatedly probed to report whether they were focusing on their breath or thinking about something else. Mind wandering episodes were associated with an increase in the amplitude and a decrease in the frequency of theta (4-8 Hz) oscillations. Conversely, alpha oscillations (8-14 Hz) were shown to decrease in amplitude and increase in frequency during mind wandering relative to breath focus. In addition, mind wandering episodes were shown to be accompanied by increased harmonicity and phase synchrony between alpha and theta rhythms. Because similar spectral changes in the theta-alpha frequency range have been reported during controlled cognitive processes involving memory and executive control, we speculate that mind wandering and controlled processes could share some neurocognitive mechanisms. From a translational perspective, this study indicates that oscillatory activity in the theta-alpha frequency range could form adequate parameters for developing EEG-neurofeedback protocols aimed at facilitating the detection of mind wandering during meditation practice.
mRNA based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus neutralizing antibodies and mediates protection in rodents
Authors: Rauch Susanne , Roth Nicole , Schwendt Kim , Fotin-Mleczek Mariola , Mueller Stefan O. , Petsch Benjamin
Published: October 2020

mRNA technologies have recently proven clinical efficacy against coronavirus disease 2019 (COVID-19) and are among the most promising technologies to address the current pandemic. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle encapsulated mRNA vaccine that encodes full length, pre-fusion stabilised severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Spike protein. In contrast to previously published approaches, CVnCoV is exclusively composed of naturally occurring nucleotides. Immunisation with CVnCoV induced strong humoral responses with high titres of virus neutralizing antibodies and robust T cell responses. CVnCoV vaccination protected hamsters from challenge with wild type SARS-CoV-2, demonstrated by the absence of viral replication in the lungs. Hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication exhibited no evidence of vaccine enhanced disease. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.
Establishment of a simplified preparation method for single-nucleus RNA-sequencing and its application to long-term frozen tumor tissues
Authors: Ernst Kati J. , Okonechnikov Konstantin , Bageritz Josephine , Mallm Jan-Philipp , Wittmann Andrea , Maaß Kendra K. , Leible Svenja , Boutros Michael , Pfister Stefan M. , Zuckermann Marc , Jones David T.W.
Published: October 2020

Recent advances allowing the genomic analysis of individual cells from a bulk population have provided intriguing new insights into areas such as developmental processes and tumor heterogeneity. Most approaches to date, however, rely on the availability of fresh surgical specimens, thereby dramatically reducing the ability to profile particularly rare tissue types. Pediatric central nervous system tumors – the leading cause of childhood cancer deaths – represent one such example, where often only frozen rather than native material is available. Due to an increasing need for advanced techniques to understand the heterogeneity of these tumors, we optimized a method to isolate intact nuclei from long-term frozen pediatric glioma tissues. We performed a technical comparison between different single nucleus RNA-sequencing (snRNA-seq) systems using a patient-derived xenograft model as a test sample. Further, we applied the established nucleus isolation method to analyze frozen primary tissue from two pediatric central nervous system tumors – one pilocytic astrocytoma and one glioblastoma – allowing the identification of distinct tumor cell populations and infiltrating microglia. The results show that our fast, simple and low-cost nuclear isolation protocol provides intact nuclei, which can be used in both droplet-based 3’ transcriptome amplification (10X Genomics) and plate-based whole transcriptome amplification (Fluidigm C1) single-cell sequencing platforms, thereby dramatically increasing the potential for application of such methods to rare entities.
Oral immunization of broilers with chitosan nano-encapsulated extracellular and cell wall proteins of necrotic enteritis-inducedClostridium perfringens
Authors: Ramadan Nour Muinis , Akerele Gabriel , Renu Sankar , Renukaradhya Gourapura , Selvaraj Ramesh
Published: October 2020

Currently, there is no commercial vaccine to controlClostridium perfringens(CP) or necrotic enteritis – a clinically and economically devastating disease. Two chitosan-nanoparticle encapsulated CP (CNP-CP) vaccines using extracellular proteins (ECP) and cell wall proteins (CWP) were synthesized: a CNP-CP ECP + CWP vaccine (SC vaccine) and a CNP-CP ECP + CWP surface-adsorbed CWP vaccine (SCC vaccine). The experiment comprised a complete randomized design of 3 treatments replicated 5 times: SC, SCC and nonimmunized control. Broilers orally gavaged with SC or SCC vaccine were primed and boosted with 70μg dose at 3- and 14-days post-hatch (dph). SDS-PAGE analysis revealed bands at 54.7 and 84.7 kDa in the ECP and 17 bands for CWP fraction. There were no differences in body weight gain, feed conversion ratio and mortality rate between treatments. At 17dph, serum of birds in the SC and SCC groups had higher neutralizing antibodies (P<0.01) compared to the control group. At 17dph, there was an increase in bile anti-ECP IgA levels in the SC vaccinated birds and a non-significant increase in SCC vaccinated birds compared to control. At 17dph, bile specific anti-CP CWP IgA levels were greater (P<0.05) in both immunized groups compared to control. At 17 and 21dph, serum anti-ECP and anti-CP CWP IgY levels in SC and SCC birds were comparable to the control. At 21dph, CD4+/CD8+ T-cell ratio in SC and SCC vaccinated groups were elevated (P≤0.01) compared to control. At 17dph, SC and SCC vaccinated birds had a significant reduction(P≤0.001)in α-toxin levels in caecal contents compared to control. Caecal α-toxin levels remained reduced at 21dph(P<0.05)in SC birds and numerically reduced in SCC vaccinated birds compared to control. Jejunal CP load in SCC birds was significantly reduced by 1.4 Log10copy numbers of CP/g compared to control and no differences were observed in liver CP load between immunized and non-immunized birds. SC and SCC immunization did not alter TNF-α, IL-10, iNOS, IL-6 or IL-17 mRNA expression. At 17 and 21dph, SC and SCC immunized birds demonstrated greater sera bactericidal activity compared to control. CNP-SC and CNP-SCC immunization induced specific immune response againstC. perfringensand reduced CP colonization via oral route of administration.
Lactate transport at the uteroplacental unit- A theoretical study
Authors: Barta Efrath
Published: October 2020

Deciphering the lactate transport within the uteroplacental unit should be aided by a theoretical model in light of the insurmountable difficulties involved with in-vivo relevant measurements. Here we formulate a boundary value problem that predicts the direction and extent of lactate fluxes within the human placenta under various physiological conditions. It accounts for metabolic processes within the placenta and transporters’ activity at the two membranes that confine the terminal villi. Lactate concentration inside the terminal villi and its fluxes at the membranes are being computed. Under normal conditions lactate flux from fetal arterioles to the placenta surpasses the flux to the fetus via the umbilical vein. Within the placenta, it adds to the lactate that originates in the glycolysis, some of it degrades to pyruvate and surpluses are delivered to the maternal circulation. The apparent permeabilities of the placental membranes with respect to lactate as well as the specific characterizations of the placental lactate production, hitherto unknown, are being estimated. We determine the range of parameter values that induce sustainable, healthy fetal lactate levels and demonstrate the versatility of lactate exchange between the placenta and the fetus by computing the effect of extreme conditions (e.g., cesarean section, intrauterine growth restriction) on lactate fluxes.
Human mobility at Tell Atchana (Alalakh) during the 2nd millennium BC: integration of isotopic and genomic evidence
Authors: Ingman Tara , Eisenmann Stefanie , Skourtanioti Eirini , Akar Murat , Ilgner Jana , Gnecchi Ruscone Guido Alberto , le Roux Petrus , Shafiq Rula , Neumann Gunnar U. , Keller Marcel , Freund Cäcilia , Marzo Sara , Lucas Mary , Krause Johannes , Roberts Patrick , Yener K. Aslıhan , Stockhammer Philipp W.
Published: October 2020

The Middle and Late Bronze Age Near East, a period roughly spanning the second millennium BC (ca. 2000-1200 BC), is frequently referred to as the first ‘international age’, characterized by intense and far-reaching contacts between different entities from the eastern Mediterranean to the Near East and beyond. In a large-scale tandem study of stable isotopes and ancient DNA of individuals excavated at Tell Atchana (Alalakh), situated in the northern Levant, we explore the role of mobility at the capital of a regional kingdom. We generated strontium isotope data for 53 individuals, oxygen isotope data for 77 individuals, and added ancient DNA data from 9 new individuals to a recently published dataset of 28 individuals. A dataset like this, from a single site in the Near East, is thus far unparalleled in terms of both its breadth and depth, providing the opportunity to simultaneously obtain an in-depth view of individual mobility and also broader demographic insights into the resident population. The DNA data reveals a very homogeneous gene pool, with only one outlier. This picture of an overwhelmingly local ancestry is consistent with the evidence of local upbringing in most of the individuals indicated by the isotopic data, where only five were found to be ‘non-local’. High levels of contact, trade, and exchange of ideas and goods in the Middle and Late Bronze Ages, therefore, seem not to have translated into high levels of individual mobility detectable at Tell Atchana.
FUNGI DIVERSITY IN THE RHIZOSPHERE OFAspilia prulisetaSchweif. ext Schweif IN THE SEMI-ARID EASTERN KENYA
Authors: Muchoka James Peter , Mugendi Daniel Njiru , Njiruh Paul Nthakanio , Mbugua Paul Kamau , Njeru Ezekiel Mugendi , Ghilamicael Amanuel Menghs , Mutiga Mariciano Iguna
Published: October 2020

Semi-arid eastern Kenya is a fragile ecosystem with continuous cultivation of dryland pulses and grains. Farmers use artificial fertilizers most of which are deleterious to the environment. Previous studies have shown that soil microbes in the rhizosphere could be used to sustainably enhance levels of soil mineral nutrients and soil health. However, few studies have examined fungal diversity in the rhizosphere of wild and nativeAspilia prulisetashrub. In this study, amplicons of Internal Transcribed Spacer (ITS) region on Total Community DNA using Illumina sequencing were used to explore the fungal community composition within the rhizosphere. Operational taxonomic units (OTUs) were analyzed using QIIME 1.8.0, taxonomy assigned via BLASTn against SILVA 119 database. Hierarchical clustering was done using R programming software. 72,093, 50,539 and 43,506 sequence reads were obtained from samples MC1a, MC2aand MC3arespectively representing rhizosphere depth 0-20 cm, 21-40 cm and 41-60 cm. A total of 373 OTUs were realized at 3% genetic distance. Taxonomic analysis revealed that the generaGlomuswas most prevalent in all soil depths with 85.60 % of the OTUs in depth 0-20 cm, 69.04 % in depth 21-40 cm and 48.45 % in depth 41-60 cm. The results revealed high levels of obligate arbuscular mycorrhiza fungi that if commercially cultured could enhance phosphates uptake in crops.
Direct visualization of native infectious SARS-CoV-2 and its inactivation forms using high resolution Atomic Force Microscopy
Authors: Lyonnais Sébastien , Hénaut Mathilde , Neyret Aymeric , Merida Peggy , Cazevieille Chantal , Gros Nathalie , Chable-Bessia Christine , Muriaux Delphine
Published: October 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for COVID19, a new emerging pandemic affecting humans. Here, single viruses were analyze by atomic force microscopy (AFM) operating directly in a level 3 biosafety (BSL3) facility, which appeared as a fast and powerful method to assess infectious virus morphology in its native conformation, or upon inactivation treatments, at the nanoscale level and in 3D. High resolution AFM reveals structurally intact infectious and inactivated SARS-CoV-2 upon low concentration of formaldehyde treatment. This protocol allows the preparation of intact inactivated SARS-CoV-2 particles for safe use of samples out of level 3 laboratory, as revealed by combining AFM and plaque assays, to accelerate researches against the COVID-19 pandemic. Overall, we illustrate how adapted BSL3-atomic force microscopy is a remarkable toolbox for rapid and direct virus identification and characterization.
Trehalose and α-glucan mediate distinct abiotic stress responses inPseudomonas aeruginosa
Authors: Woodcock Stuart D. , Syson Karl , Little Richard H. , Sifouna Despoina , Brown James K.M. , Bornemann Stephen , Malone Jacob G.
Published: October 2020

An important prelude to bacterial infection is the ability of a pathogen to survive independently of the host and to withstand environmental stress. The compatible solute trehalose has previously been connected with diverse abiotic stress tolerances, particularly osmotic shock. In this study, we combine molecular biology and biochemistry to dissect the trehalose metabolic network in the opportunistic human pathogenPseudomonas aeruginosaPA01 and define its role in abiotic stress protection. We show that trehalose metabolism in PA01 is integrated with the biosynthesis of branched α-glucan (glycogen), with mutants in either biosynthetic pathway significantly compromised for survival on abiotic surfaces. While both trehalose and α-glucan are important for abiotic stress tolerance, we show they counter distinct stresses. Trehalose is vital to the PA01 osmotic stress response, with trehalose synthesis mutants displaying severely compromised growth in elevated salt conditions. However, trehalose does not contribute directly to the PA01 desiccation response. Rather, desiccation tolerance is mediated directly by GlgE-derived α-glucan, with deletion of theglgEsynthase gene compromising PA01 survival in low humidity but having little effect on osmotic sensitivity. Desiccation tolerance is independent of trehalose concentration, marking a clear distinction between the roles of these two molecules in mediating responses to abiotic stress.
Piggybacking on niche-adaptation reduces the cost of multidrug resistance plasmids
Authors: Kloos Julia , Gama João A. , Hegstad Joachim , Samuelsen Ørjan , Johnsen Pål J.
Published: October 2020

The persistence of plasmids in bacterial populations represents a puzzling evolutionary problem with serious clinical implications due to their role in the ongoing antibiotic resistance crisis. Recently, major advancements have been made towards resolving this “plasmid paradox” but mainly in a non-clinical context. Here we propose an additional explanation for the maintenance of multidrug resistance (MDR) plasmids in clinicalEscherichia colistrains. After co-evolving two MDR plasmids encoding last resort carbapenem resistance with an extraintestinal pathogenicE. colistrain, we observed that chromosomal media adaptive mutations in the global regulatory systems CCR (Carbon Catabolite Repression) and ArcAB (Aerobic Respiration Control) pleiotropically mitigated the costs of both plasmids. Mechanistically, cost reductions were due to a net downregulation of plasmid gene expression. Our results suggest that global chromosomal transcriptional re-wiring during bacterial niche-adaptation may facilitate plasmid maintenance.
Spontaneous emergence of azithromycin resistance in independent lineages ofSalmonellaTyphi in Northern India
Authors: Carey Megan E. , Jain Ruby , Yousuf Mohammad , Maes Mailis , Dyson Zoe A. , Thu Trang Nguyen Hoang , Nguyen To Nguyen Thi , Dan Thanh Ho Ngoc , Nguyen Quynh Nhu Pham , Mahindroo Jaspreet , Pham Duy Thanh , Sandha Kawaljeet Singh , Baker Stephen , Taneja Neelam
Published: October 2020

Background

The emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug resistant (XDR)SalmonellaTyphi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin resistantS. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal.

Methods

Here, we aimed to understand the molecular basis of AMR in 66S. Typhi isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole genome sequencing (WGS) and phylogenetic analysis.

Results

We identified sevenS. Typhi organisms with the R717Q mutation in theacrBgene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the azithromycin-resistantS. Typhi isolates also exhibited triple mutations ingyrA(S83F and D87N) andparC(S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal.

Conclusions

The independent emergence of azithromycin resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines (TCVs) in the region.

Key points

We identified ciprofloxacin/azithromycin-resistantSalmonellaTyphi (S. Typhi) in Chandigarh in Northern India. The independent emergence of ciprofloxacin/azithromycin-resistant typhoid in Bangladesh, Pakistan, Nepal, and India and the continued spread of extensively-drug resistant (XDR) typhoid in Pakistan highlight the limitations of licensed oral treatments for typhoid fever in South Asia.
Efficient long-range conduction in cable bacteria through nickel protein wires
Authors: Boschker Henricus T. S. , Cook Perran L.M. , Polerecky Lubos , Eachambadi Raghavendran Thiruvallur , Lozano Helena , Hidalgo-Martinez Silvia , Khalenkow Dmitry , Spampinato Valentina , Claes Nathalie , Kundu Paromita , Wang Da , Bals Sara , Sand Karina K. , Cavezza Francesca , Hauffman Tom , Bjerg Jesper Tataru , Skirtach Andre G. , Kochan Kamila , McKee Merrilyn , Wood Bayden , Bedolla Diana , Gianoncelli Alessandra , Geerlings Nicole M.J. , Gerven Nani Van , Remaut Han , Geelhoed Jeanine S. , Millan-Solsona Ruben , Fumagalli Laura , Nielsen Lars-Peter , Franquet Alexis , Manca Jean V. , Gomila Gabriel , Meysman Filip J. R.
Published: October 2020

Filamentous cable bacteria display unrivalled long-range electron transport, generating electrical currents over centimeter distances through a highly ordered network of fibers embedded in their cell envelope. The conductivity of these periplasmic wires is exceptionally high for a biological material, but their chemical structure and underlying electron transport mechanism remain unresolved. Here, we combine high-resolution microscopy, spectroscopy, and chemical imaging on individual cable bacterium filaments to demonstrate that the periplasmic wires consist of a conductive protein core surrounded by an insulating shell layer. The core proteins contain a sulfur-ligated nickel cofactor, and conductivity decreases when nickel is oxidized or selectively removed. The involvement of nickel as the active metal in biological conduction is remarkable, and suggests a hitherto unknown form of electron transport that enables efficient conduction in centimeter-long protein structures.
A unified physiological framework of transitions between seizures, sustained ictal activity and depolarization block at the single neuron level
Authors: Depannemaecker Damien , Ivanov Anton , Lillo Davide , Spek Len , Bernard Christophe , Jirsa Viktor
Published: October 2020

The majority of seizures recorded in humans and experimental animal models can be described by a generic phenomenological mathematical model, The Epileptor. In this model, seizure-like events (SLEs) are driven by a slow variable and occur via saddle node (SN) and homoclinic bifurcations at seizure onset and offset, respectively. Here we investigated SLEs at the single cell level using a biophysically relevant neuron model including a slow/fast system of four equations. The two equations for the slow subsystem describe ion concentration variations and the two equations of the fast subsystem delineate the electrophysiological activities of the neuron. Using extracellular K+as a slow variable, we report that SLEs with SN/homoclinic bifurcations can readily occur at the single cell level when extracellular K+reaches a critical value. In patients and experimental models, seizures can also evolve into sustained ictal activity (SIA) and, depolarization block (DB), activities which are also parts of the dynamic repertoire of the Epileptor. Increasing extracellular concentration of K+in the model to values found during experimental status epilepticus and DB, we show that SIA and DB can also occur at the single cell level. Thus, seizures, SIA and DB, which have been first identified as network events, can exist in a unified framework of a biophysical model at the single neuron level and exhibit similar dynamics as observed in the Epileptor.

Author Summary

Epilepsy is a neurological disorder characterized by the occurrence of seizures. Seizures have been characterized in patients in experimental models at both macroscopic and microscopic scales using electrophysiological recordings. Experimental works allowed the establishment of a detailed taxonomy of seizures, which can be described by mathematical models. We can distinguish two main types of models. Phenomenological (generic) models have few parameters and variables and permit detailed dynamical studies often capturing a majority of activities observed in experimental conditions. But they also have abstract parameters, making biological interpretation difficult. Biophysical models, on the other hand, use a large number of variables and parameters due to the complexity of the biological systems they represent. Because of the multiplicity of solutions, it is difficult to extract general dynamical rules. In the present work, we integrate both approaches and reduce a detailed biophysical model to sufficiently low-dimensional equations, and thus maintaining the advantages of a generic model. We propose, at the single cell level, a unified framework of different pathological activities that are seizures, depolarization block, and sustained ictal activity.
Transcriptional silencing ofALDH2in acute myeloid leukemia confers a dependency on Fanconi anemia proteins
Authors: Yang Zhaolin , Wei Yiliang , Wu Xiaoli S. , Iyer Shruti V. , Jung Moonjung , Adelman Emmalee R. , Klingbeil Olaf , Kramer Melissa , Demerdash Osama E. , Chang Kenneth , Goodwin Sara , Hodges Emily , McCombie W. Richard , Figueroa Maria E. , Smogorzewska Agata , Vakoc Christopher R.
Published: October 2020

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitin conjugation and ligation machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing ofALDH2occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse
Authors: Balmer Timothy S. , Borges-Merjane Carolina , Trussell Laurence O.
Published: October 2020

Synapses of glutamatergic mossy fiber onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBC. The source of ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Changing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.
Environmental enrichment enhances patterning and remodeling of synaptic nanoarchitecture revealed by STED nanoscopy
Authors: Wegner Waja , Steffens Heinz , Gregor Carola , Wolf Fred , Willig Katrin I.
Published: October 2020

Synaptic plasticity underlies long-lasting structural and functional changes to brain circuitry and its experience-dependent remodeling can be fundamentally enhanced by environmental enrichment. It is unknown, however, whether and how environmental enrichment alters the morphology and dynamics of individual synapses. Here, we present a virtually crosstalk free, two-colorin vivoSTED microscope to simultaneously superresolve the dynamics of endogenous PSD95 of the post-synaptic density and spine geometry. With environmental enrichment, the size distributions of PSD95 and spine head sizes were sharper than in controls, indicating that synaptic strength is set more precisely with environmental enrichment. Spine head geometry and PSD95 assemblies were highly dynamic but their changes correlated only mildly. With environmental enrichment, the topography of the PSD95 nanoorganization was more dynamic; changes in size were smaller than in mice housed in standard cages and depended linearly on their original size. Thus, two-colorin vivotime-lapse imaging of synaptic nanoorganization uncovers a unique synaptic nanoplasticity associated with the enhanced learning capabilities under environmental enrichment.
Sound transmission by chamber prosthesis of the middle ear
Authors: Gambin Wiktor L.
Published: October 2020

Tests done on specimens cut from the temporal bones show, that the stapedotomy can be more effective, if instead of the piston prosthesis, the ear chamber prosthesis is used. In that case, the vibrations of the eardrum are transferred to a plate with attachment sticked to the incus. The plate is suspended on a membrane stretched on the base of conical chamber which is filled with a fluid and placed in the middle ear cave. The sound wave caused by a vibrating plate, is focused at the chamber outlet placed in a small hole drilled in the stapes footplate. As in the case of the piston prosthesis behavior of the round window membrane differs from that observed in the normal ear. The flow through a narrow outlet of the conical chamber makes a more deflection of the central part of the round window membrane. The properties of the prosthesis elements are close to those of the removed parts of the middle ear. In spite of this, one can observe a different sound transmission inside the ear. When the sound is higher than 1000 Hz, the vibration amplitude of the plate is 5-10 dB higher than that for the stapes footplate in the healthy ear. However, when the sound is lower than 1000 Hz, this amplitude is lower than that for the stapes footplate. To explain it, a simplified model of the sound propagation in the ear given in the prior work is used. To get a better agreement with the test results, the model takes into account a damping of the sound wave by the round window membrane. Next, the model is adapted to the ear with chamber prosthesis. The factors that may have an effect on the behavior of the sound wave are examined. The first is shortening of the incus. It increases the leverage of the ossicles and the force acting on the prosthesis plate compared to that in the normal ear. Next factor is a reduction of the mass of the vibrating plate what makes a growth of its resonance frequency. This slightly reduces the amplitude of the plate for the low sounds and increases it for the medium and the higher sounds. At end, the lack of the influence of the flow through the conical chamber on the sound wave energy is shown. The assumed model gives the rules for amplitudes of the chamber plate as functions of the sound frequency. Their values for the sound frequency from 400 Hz to 8000 Hz and its graphs are shown and compared with those for the stapes footplate in the normal ear. One can see that if the sound frequency is higher than 1000 Hz, then the chamber prosthesis makes higher amplitudes of the sound wave than the normal ear. To explain their drop for frequencies lower than 1000 Hz, needs more tests in this range.
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Authors: den Hoed J. , de Boer E. , Voisin N. , Dingemans A.J.M. , Guex N. , Wiel L. , Nellaker C. , Amudhavalli S.M. , Banka S. , Bena F.S. , Ben-Zeev B. , Bonagura V.R. , Bruel A.-L. , Brunet T. , Brunner H.G. , Chew H.B. , Chrast J. , Cimbalistienė L. , Coon H. ,   The DDD study, Délot E.C. , Démurger F. , Denommé-Pichon A.-S. , Depienne C. , Donnai D. , Dyment D.A. , Elpeleg O. , Faivre L. , Gilissen C. , Granger L. , Haber B. , Hachiya Y. , Abedi Y. Hamzavi , Hanebeck J. , Hehir-Kwa J.Y. , Horist B. , Itai T. , Jackson A. , Jewell R. , Jones K.L. , Joss S. , Kashii H. , Kato M. , Kattentidt-Mouravieva A.A. , Kok F. , Kotzaeridou U. , Krishnamurthy V. , Kučinskas V. , Kuechler A. , Lavillaureix A. , Liu P. , Manwaring L. , Matsumoto N. , Mazel B. , McWalter K. , Meiner V. , Mikati M.A. , Miyatake S. , Mizuguchi T. , Moey L.H. , Mohammed S. , Mor-Shaked H. , Mountford H. , Newbury-Ecob R. , Odent S. , Orec L. , Osmond M. , Palculict T.B. , Parker M. , Petersen A. , Pfundt R. , Preikšaitienė E. , Radtke K. , Ranza E. , Rosenfeld J.A. , Santiago-Sim T. , Schwager C. , Sinnema M. , Blok L. Snijders , Spillmann R.C. , Stegmann A.P.A. , Thiffault I. , Tran L. , Vaknin-Dembinsky A. , Vedovato-dos-Santos J.H. , Vergano S.A. , Vilain E. , Vitobello A. , Wagner M. , Waheeb A. , Willing M. , Zuccarelli B. , Kini U. , Newbury D.F. , Kleefstra T. , Reymond A. , Fisher S.E. , Vissers L.E.L.M.
Published: October 2020

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.