bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic Design of Pulse Dosing to Eradicate Persister Bacteria
Authors: Singh Garima , Orman Mehmet A. , Conrad Jacinta C. , Nikolaou Michael 
Published: May 2022

AbstractA small fraction of infectious bacteria use persistence as a strategy to survive exposure to antibiotics. Periodic pulse dosing of antibiotics has long been considered a potentially effective strategy towards eradication of persisters. Recent studies have demonstrated throughin vitroexperiments that it is indeed feasible to achieve such effectiveness. However, systematic design of periodic pulse dosing regimens to treat persisters is currently lacking. Here we rigorously develop a methodology for the systematic design of optimal periodic pulse dosing strategies for rapid eradication of persisters. A key outcome of the theoretical analysis, on which the proposed methodology is based, is that bactericidal effectiveness of periodic pulse dosing depends mainly on the ratio of durations of the corresponding on and off parts of the pulse. Simple formulas for critical and optimal values of this ratio are derived. The proposed methodology is supported by computer simulations andin vitroexperiments.Author SummaryAdministering antibiotics in periodic pulses that alternate between high and low concentration has long been known as a possible dosing strategy to treat stubborn infections caused by bacteria known aspersisters. Such bacteria use clever mechanisms to survive otherwise lethal temporary exposure to antibiotics and to resume normal activity upon antibiotic removal. Persisters pose a serious health problem. Recent studies have elucidated mechanisms of persistence and have confirmed that pulse dosing, if designed appropriately, can indeed be effective. However, effective pulse dosing design has been mainly handled by trial and error, requiring relatively extensive experimentation. Here we develop a method for rapid systematic design of effective pulse dosing. The method relies on a simple mathematical model and a minimal amount of standard experimental data. We derive corresponding design formulas that explicitly characterize the shape of generally effective or optimal periodic pulses. We tested our method through computer simulations andin vitroexperiments, as well as on prior literature data. In all cases, the outcomes on persister bacteria eradication predicted by our method were confirmed. These results pave the way for ultimately developing effective pulse dosing regimens in realistic situationsin vivo.
Fine-scale diversity of microbial communities due to satellite niches in boom-and-bust environments
Authors: Wang Zihan , Fridman Yulia , Maslov Sergei , Goyal Akshit 
Published: May 2022

AbstractRecent observations have revealed that closely related strains of the same microbial species can stably coexist in natural and laboratory settings subject to boom-and-bust dynamics and serial dilutions, respectively. However, the possible mechanisms enabling the coexistence of only a handful of strains, but not more, have thus far remained unknown. Here, using a consumer-resource model of microbial ecosystems, we propose that by differentiating on Monod parameters characterizing microbial growth rates in high and low nutrient conditions, strains can coexist in patterns similar to those observed. In our model, boom-and-bust environments create satellite niches due to resource concentrations varying in time. These satellite niches can be occupied by closely related strains, thereby enabling their coexistence. We demonstrate that this result is valid even in complex environments consisting of multiple resources and species. In these complex communities, each species partitions resources differently and creates separate sets of satellite niches for their own strains. While there is no theoretical limit to the number of coexisting strains, in our simulations, we always find between 1 and 3 strains coexisting, consistent with experiments and observations.Author summaryRecent genomic data has exposed to us the remarkable spectrum of microbial diversity in natural communities surrounding us, which harbor not only hundreds of species, but also a handful of closely related strains within each of those species (termed “oligo-colonization”). While the mechanisms behind species coexistence are much better studied, the mechanisms behind the coexistence of closely related strains have remained understudied. Here, using a simple consumer-resource model, we show that if strains differ on their Monod growth parameters, they can coexist even on a single limiting resource, provided that the environments vary with time in boom-and-bust cycles. The Monod growth parameters describe how a strain’s growth rate changes with resource concentration, namely the half-maximal concentration and maximal growth rate. Simulations of our model show that both in simple and complex environments, even though an arbitrary number of strains can coexist, typically it is between 1 and 3 strains of a species that coexist over several randomly assembled communities, consistent with some experimental observations. This is because the allowed parameter space for coexistence shrinks significantly with the number of strains that coexist.
coiaf: directly estimating complexity of infection with allele frequencies
Authors: Paschalidis Aris , Watson Oliver J. , Aydemir Ozkan , Verity Robert , Bailey Jeffrey A. 
Published: May 2022

AbstractIn malaria, individuals are often infected with different parasite strains; the complexity of infection (COI) is defined as the number of genetically distinct parasite strains in an individual. Changes in the mean COI in a population have been shown to be informative of changes in transmission intensity with a number of probabilistic likelihood and Bayesian models now developed to estimate the COI. However, rapid, direct measures based on heterozygosity or FwS do not properly represent the COI. In this work, we present two new methods that use easily calculated measures to directly estimate the COI from allele frequency data. Using a simulation framework, we show that our methods are computationally efficient and comparably accurate to current methods in the literature. Through a sensitivity analysis, we characterize how the bias and accuracy of our two methods are impacted by the distribution of parasite densities and the assumed sequencing depth and number of sampled loci. We further estimate the COI globally from Plasmodium falciparum sequencing data using our developed methods and compare the results against the literature. We show significant differences in estimated COI globally between continents and a weak relationship between malaria prevalence and COI.Author summaryComputational models, used in conjunction with rapidly advancing sequencing technologies, are increasingly being used to help inform surveillance efforts and understand the epidemiological dynamics of malaria. One such important metric, the complexity of infection (COI), indirectly quantifies the level of transmission. Existing “gold-standard” COI measures rely on complex probabilistic likelihood and Bayesian models. As an alternative, we have developed the statistics and software package coiaf, which features two rapid, direct measures to estimate of the number of genetically distinct parasite strains in an individual (the COI). Our methods were evaluated using simulated data and subsequently compared to current “state-of-the-art” methods, yielding comparable results. Lastly, we examined the distribution of the COI in several locations across the world, identifying significant differences in COI between continents. coiaf, therefore, provides a new, promising framework for rapidly characterizing polyclonal infections.
Orientation control strategies and adaptation to a visuomotor perturbation in rotational hand movements
Authors: Zruya Or , Nisky Ilana 
Published: May 2022

AbstractComputational approaches to biological motor control are used to discover the building blocks of human motor behavior. Models explaining features of human hand movements have been studied thoroughly, yet only a few studies attempted to explain the control of the orientation of the hand; instead, they mainly focus on the control of hand translation, predominantly in a single plane. In this study, we aimed to establish a basic understanding of the way humans control the orientation of their hands. We developed a quaternion-based score that quantifies the geodicity of rotational hand movements and evaluated it experimentally. In the first experiment participants performed a simple orientation-matching task with a robotic manipulator. We found that rotations are generally performed by following a geodesic in the quaternion hypersphere, which suggests that, similarly to translation, the orientation of the hand is centrally controlled. We also established a baseline for the study of human response to perturbed visual feedback of the orientation of the hand. In the subsequent second experiment we studied the adaptation of participants to visuomotor rotation that is applied on the hand’s rotation, and the transfer of the adaptation to a different initial orientation. We observed partial adaptation to the perturbation. The patterns of the transfer of the adaptation to a different initial orientation were consistent with the representation of the orientation in extrinsic coordinates. The results of the two experiments raise questions regarding the nature of central control of hand orientation. Discussion and intuitions from these results can be of benefit for many applications that involve fine manipulation of rigid bodies, such as teleoperation and neurorehabilitation.Author summaryDaily motor actions, as simple as pouring a glass of wine or as complicated as playing a violin, require coordinated activation of multiple muscles that synchronize to produce a precise motion of the hand. Controlled by sensorimotor areas in the central nervous system, our muscles can translate and rotate our hand from one posture to another. Our study focused on the very basis of the control of orientation: we attempted to reveal which variables are centrally controlled when we rotate our hand. The discovery that simple rotations are generally performed along a geometrically optimal path established a baseline for studying the response to rotation-based perturbations. By visually remapping the orientation of the hand, we found that humans perceive their hand’s orientation in visual, rather than joint-based coordinates. These findings have implications for the design of human-centered control systems for teleoperation, where visual distortions may occur, and for the design of rehabilitation devices for people with motor impairments.
The evolution of manipulative cheating
Authors: Liu Ming , West Stuart A. , Wild Geoff 
Published: May 2022

AbstractA social cheat is typically assumed to be an individual that does not perform a cooperative behaviour, or performs less of it, but can still exploit the cooperative behaviour of others. However, empirical data suggests that cheating can be more subtle, involving evolutionary arms races over the ability to both exploit and resist exploitation. These complications have not been captured by evolutionary theory, which lags behind empirical studies in this area. We bridge this gap with a mixture of game-theoretical models and individual-based simulations, examining what conditions favour more elaborate patterns of cheating. We found that as well as adjusting their own behaviour, individuals can be selected to manipulate the behaviour of others, which we term ‘manipulative cheating’. Further, we found that manipulative cheating can lead to dynamic oscillations (arms races), between selfishness, manipulation, and suppression of manipulation. Our results can help explain both variation in the level of cheating, and genetic variation in the extent to which individuals can be exploited by cheats.
Facilitation by a hERG blocker is induced by pore opening and operates by pore reopening
Authors: Furutani Kazuharu , Kawano Ryotaro , Ichiwara Minami , Adachi Ryo , Clancy Colleen E. , Sack Jon T. , Kita Satomi 
Published: May 2022

AbstractA drug that blocks the cardiac myocyte voltage-gated K+channels encoded by the human Ether-à-go-go-Related Gene (hERG) carries a potential risk of long QT syndrome and life-threatening cardiac arrhythmia, includingTorsade de Points. Interestingly, certain hERG blockers can also facilitate hERG activation to increase hERG currents, which may reduce proarrhythmic potential. However, the molecular mechanism involved in the facilitation effect of hERG blockers remains unclear. The hallmark feature of the facilitation effect by hERG blockers is that a depolarizing preconditioning pulse shifts voltage-dependence of hERG activation to more negative voltages. Here we utilize a D540K hERG mutant to study the mechanism of the facilitation effect. D540K hERG is activated by not only depolarization but also hyperpolarization. This unusual gating property of the D540K hERG channel enables testing of hypotheses about the mechanism by which voltage induces facilitation of hERG by blockers. With D540K hERG, we find that nifekalant, a hERG blocker and Class III antiarrhythmic agent, facilitates not only current activation by depolarization but also current activation by hyperpolarization. Our results indicate that induction of facilitation is coupled to pore opening, not voltageper se. We propose that a gated-access mechanism is involved in the voltage-dependence of induction of facilitation. This study provides a molecular mechanism for modulation of hERG channels by nifekalant, a clinically important antiarrhythmic agent.Significance statementNifekalant is a clinically important antiarrhythmic agent and a hERG blocker which can also facilitate voltage-dependent activation of hERG channels after a preconditioning pulse. Here we show that the mechanism of action of the preconditioning pulse is to open a conductance gate to enable drug access to a facilitation site. Moreover, we find that facilitation increases hERG currents by altering pore dynamics, rather than acting through voltage sensors.
Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis
Authors: Alli Abdel A , Desai Dhruv , Elshika Ahmed , Morel Laurence , Conrad Marcus , Proneth Bettina , Clapp William , Atkinson Carl , Segal Mark , Searcy Louis A. , Denslow Nancy D. , Bolisetty Subhashini , Mehrad Borna , Scindia Yogesh 
Published: May 2022

AbstractObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Iron accumulates in the kidney tubules of nephritic patients and lupus-prone nephritic mice. Ferroptosis is a druggable, iron-dependent form of cell death that has received little attention in lupus nephritis. This study investigated whether intra-renal ferroptosis is a target for intervention in lupus nephritis.MethodsKidneys of lupus nephritis patients and two spontaneous murine models of lupus nephritis were characterized for ferroptosis using protein, RNA, and lipidomics-based approaches. Susceptibility of heavy chain ferritin (FtH1; an essential iron sequestration protein) deficient proximal tubular epithelial cells (PTECs) was studied using nephrotoxic serum nephritis and FtH1 knockdown human PTECs. The benefit of Liproxstatin-2, a novel second-generation ferroptosis, was evaluated using human PTECs exposed to lupus nephritis patients’ serum.ResultsHuman and murine nephritic kidneys have the characteristic markers of ferroptosis, such as 4-hydroxynonenal and acyl-CoA synthetase long-chain family member 4, mainly in the tubular segments. Murine kidneys showed impairment in the glutathione synthesis pathway, decreased expression of glutathione peroxidase 4, a glutathione-dependent ferroptosis inhibitor, and characteristic ferroptotic lipid signature. Loss of FtH1 increased PTEC pathology independent of glomerular injury. These findings were recapitulated in human PTECs. Of translational relevance, Liproxstatin-2 demonstrated a prophylactic and therapeutic benefit in mitigating lupus nephritis patient serum-induced PTEC ferroptosis.ConclusionOur findings highlight tubular cell ferroptosis as a pathological feature in human and murine lupus nephritis and identify ferroptosis inhibitors as potential novel adjunct therapeutics to treat lupus nephritis.
Hippocampal Concentrations Drive Seizures in a Rat Model for Cefepime-induced Neurotoxicity
Authors: Lesnicki Emily , Pais Gwendolyn M. , Marianski Sylwia , Valdez Kimberly , Gibson Zoe , Christopher Jeffri , Scheetz Marc H. 
Published: May 2022

BackgroundIn high dose, cefepime causes neurotoxicity in patients with kidney injury; however, the relationship between exposure and observed neurotoxicity is not clear, and no animal model presently recapitulates the human condition.ObjectivesThis study sought to describe plasma and tissue pharmacokinetics and pharmacodynamics (PK/PD) of cefepime in rats experiencing neurotoxicity.MethodsMale Sprague-Dawley rats (n=21) received escalating cefepime total daily doses ranging from 531-1593 mg/kg body weight/day administered as a short infusion (0.5 mL/min) every 24h for 5 days. Cefepime was quantified in plasma, cerebral cortex and hippocampus via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple PK/PD models of cefepime transit between plasma and brain compartments (i.e. cerebral cortex and hippocampus) and neurotoxic response were explored using Monolix 2021R1 (LixoftPK).ResultsExposure estimation of cerebral cortex demonstrated a median (IQR) AUC0 –24 and Cmax 0 –24 of 181.8 (85.2-661.3) mg · 24 h/liter and 13.9 (1.0-30.1) mg/L, respectively. The median cerebral cortex/blood percentage of penetration was 1.7%. Exposure estimation of hippocampus demonstrated a median (IQR) AUC0 –24 and Cmax 0 –24 of 291.4 (126.6-1091.6) mg · 24 h/liter and 8.8 (3.4-33.4) mg/L, respectively. The median hippocampus/blood percentage of penetration was 4.5%. Rats that reached a cefepime Cmax of □17 mg/L in the hippocampus exhibited signs of neurotoxicity. A hippocampal cefepime concentration of 4.1 µg/100 mg brain tissue best described seizure stages >1 for cefepime-induced neurotoxicty.ConclusionsA cefepime plasma AUC0 –24 of 28,000 mg•24h/L and hippocampal concentrations of 4.1 µg/100 mg brain tissue may be a threshold for cefepime-induced neurotoxicity. This model provides a methodology for future interrogation of the relationship between plasma concentrations, brain tissue concentrations, and neurotoxicity.
Signal Transformations and New Timing Rules of Hippocampal CA3 to CA1 Synapses
Authors: Gattas Sandra , Le Aliza A. , Abadchi Javad Karimi , Pruess Ben , Shen Yanning , Swindlehurst A. , Yassa Michael A. , Lynch Gary S. 
Published: May 2022

AbstractThe synapse is the fundamental unit of communication in the nervous system. Determining how information is transferred across the synaptic interface is one of the most complex endeavors in neuroscience, owing to the large number of contributing factors and events. An approach to solving this problem involves collapsing across these complexities to derive concise mathematical formulas that fully capture the governing dynamics of synaptic transmission. We investigated the feasibility of deriving such a formula – an input-output transformation function for the CA3 to CA1 node of the hippocampus -- using the Volterra expansion technique for nonlinear system identification. The entirety of the field EPSP in the apical dendrites of mouse brain slices was described with >94% accuracy by a 2nd order equation that captured the linear and nonlinear influence of past inputs on current outputs. This function generalized to cases not included in its derivation and uncovered previously undetected timing rules. The basal dendrites expressed a substantially different transfer function and evidence was obtained that, unlike the apical system, a 3rd order system or higher will be needed for complete characterization. Collectively, these results describe a readily implemented and unusually sensitive means for evaluating the effects of pharmacological treatments and disease related conditions on synaptic dynamics. At scale, the approach will also provide information needed for the construction of biologically realistic models of brain networks.
Hippocampal place cell remapping occurs with memory storage of aversive experiences
Authors: Blair Garrett J. , Guo Changliang , Wang Shiyun , Fanselow Michael S. , Golshani Peyman , Aharoni Daniel , Blair Hugh T. 
Published: May 2022

ABSTRACTAversive stimuli can cause hippocampal place cells to remap their firing fields, but it is not known whether remapping plays a role in storing memories of aversive experiences. Here we addressed this question by performingin-vivocalcium imaging of CA1 place cells in freely behaving rats (n=14). Rats were first trained to prefer a short path over a long path for obtaining food reward, then trained to avoid the short path by delivering a mild footshock. Remapping was assessed by comparing place cell population vector similarity before acquisition versus after extinction of avoidance. Some rats received shock after systemic injections of the amnestic drug scopolamine at a dose (1 mg/kg) that impaired avoidance learning but spared spatial tuning and shock-evoked responses of CA1 neurons. Place cells remapped significantly more following remembered than forgotten shocks (drug-free versus scopolamine conditions); shock-induced remapping did not cause place fields to migrate toward or away from the shocked location and was similarly prevalent in cells that were responsive versus non-responsive to shocks. When rats were exposed to a neutral barrier rather than aversive shock, place cells remapped significantly less in response to the barrier. We conclude that place cell remapping occurs in response to events that are remembered rather than merely perceived and forgotten, suggesting that reorganization of hippocampal population codes may play a role in storing memories for aversive events.