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Over 40 years of accumulated research has detailed associations between neuroimaging signals measured during a memory encoding task and later memory performance, across a variety of brain regions, measurement tools, statistical approaches and behavioral tasks. But the interpretation of these Subsequent Memory Effects (SMEs) remains unclear: if the identified signals reflect cognitive and neural mechanisms of memory encoding then the underlying neural activity must be causally related to future memory. However, almost all previous SME analyses do not control for potential confounders of this causal interpretation, such as serial position and item effects. We collect a large fMRI dataset and use a novel experimental design and analysis approach that allows us to statistically adjust for all exogenous confounding variables. We find that, using standard approaches without adjustment, we replicate several univariate and multivariate subsequent memory effects and are able to predict memory performance across people. However, we are unable to identify any signal that reliably predicts subsequent memory after adjusting for confounding variables, bringing into doubt the causal status of these effects. We apply the same approach to subjects’ judgments of learning collected during an encoding period, and show that these behavioral measures of encoding quality do predict memory after adjustments, suggesting that it is possible to measure signals at the time of encoding that reflect causal mechanisms but that existing neuroimaging measures may not have the precision and specificity to do so.

Arcuate line hernias are a rare type of hernia with limited publications regarding their successful repair. The arcuate line is the inferior limit of the posterior leaf of the rectus sheath. An arcuate line hernia is a type of intraparietal hernia, meaning it is not a truly complete fascial defect of the abdominal and, therefore, may present with atypical symptoms. Although published data on arcuate line hernia repairs are limited to a handful of case reports and one literature review, reports regarding robotic repair are exceptionally rare. This case report is the second documented robotic approach to arcuate line hernias known to these authors.

In 1976, a pilot experiment, called first Equatorial Mooring (EQUA-1), tested an innovative technique for anchoring a taut-line surface mooring at 0°, 150°W where the water depth is 4.5 km. The 36-day deployment contained a wind recorder and fixed-level current meters at 50 and 100 m in the Equatorial Undercurrent (EUC). The following year, in a second pilot experiment, named EQUA-2, a similar mooring was deployed at 0°, 125°W for 99 days. EQUA-2, with current meters at 10, 50, 100, 150, and 200 m, recorded a surge in EUC transport during April 1977 when 3-day-averaged eastward current speeds at 50-m depth reached 2 m s−1. The associated eastward transport per unit meridional width over the 50–200-m layer was 190 m2 s−1. Based on observations recorded in April 1980, the EQUA-2 pulse would correspond to a total EUC transport surge of about 38 Sv (1 Sv ≡ 106 m3 s−1) and would represent an equatorially trapped first-mode baroclinic Kelvin wave. This paper describes EQUA Project observations and why and how I created the high-risk-of-failure opportunity to record pioneering time series measurements at the equator. The enduring legacy of the EQUA Project is the sustained maintenance of in situ surface wind and upper-ocean current and temperature measurements at numerous sites in the equatorial oceans, starting in the Pacific to improve forecasts of the El Niño and La Niña phenomenon. For example, the 40-yr records of surface wind and upper-ocean current and temperature measurements at 0°, 110°W and 0°, 140°W are some of oceanography’s longest time series recorded far from land.

A crucial step in antimicrobial development pipelines is proof of functionality in the host environment. Antibiotics targeting fatty acid synthesis (FASII) of the major pathogen Staphylococcus aureus actively inhibit FASII but do not prevent in vivo growth, as bacteria compensate the FASII block by using environmental fatty acids. We report that S. aureus responds to FASII antibiotic treatment by major shifts in expression that correlate with improved fitness but decreased virulence, and with altered bacterial killing in an insect infection model. Proteomic kinetics and phosphoproteomic analyses show that anti-FASII provokes massive protein reprogramming compared to non-treated S. aureus, while growth is robust in both conditions. Anti-FASII adaptation leads to overall increases in stress response functions and provides greater resistance to peroxide, as produced during host infection. Moreover, S. aureus adaptation to anti-FASII is accelerated by pre-treatment with peroxides. In contrast, virulence factor levels are decreased. In keeping with the observed phenotypes, anti-FASII-adapted S. aureus are slower to kill their host in a Galleria mellonella infection model than non-treated bacteria, but are not eliminated. Thus, anti-FASII adapted cells might be better prepared for survival and less equipped to damage the host. If not eliminated, anti-FASII reprogrammed S. aureus populations might provide a bacterial reservoir for the emergence of chronic infections.Author SummaryBacterial resistance or adaptation to currently used antibiotics is a main reason for treatment failure. Our work on the major human pathogen Staphylococcus aureus revealed that antibiotics targeting fatty acid synthesis (FASII) effectively reach their targets, but do not stop growth. Here we analyzed the expression and infection capacities of S. aureus populations that escape anti-FASII inhibition by adapting to the antibiotic. Remarkably, anti-FASII-adapted bacteria show massive expression changes, but grow normally. Once adapted, bacteria produce greater amounts of stress response proteins, while virulence factor levels or activities are lower. Accordingly, anti-FASII-adapted S. aureus provoke slower killing in an insect infection model, but bacteria continue to multiply. If not eliminated, anti-FASII reprogrammed S. aureus populations could provide a bacterial reservoir for establishment of chronic infections.

Objective: Much of our knowledge concerning the neural basis of human memory derives from lab-based verbal recall tasks. Outside of the lab, clinicians use validated and normed neuropsychological tests to assess patients' memory function and to evaluate clinical interventions. Here we sought to establish the clinical validity of multi-trial free recall of semantically organized and unrelated word lists. Methods: We compared memory performance in multi-trial free recall tasks with the Rey Auditory Verbal Learning Task (RAVLT) and the California Verbal Learning Task (CVLT), two common neuropsychological tests aimed at evaluating memory function in clinical settings. We compared predictive validity between the tasks by (a) evaluating deficits in a patient sample, (b) examining age-related declines in memory. We also compared test-retest reliability, convergent validity and the emergence of common recall dynamics between the tasks. Results: We demonstrate that both laboratory free recall tasks have better predictive validity, as well as test-retest reliability, than the established neuropsychological tests. We further show that all tasks have good convergent validity and reveal core memory processes, including temporal and semantic organization, but we demonstrate the benefits of repeated trials for evaluating the dynamics of memory search and their neuropsychological sequelae. Conclusion: The results provide evidence for the clinical validity of lab-based multi-trial free recall tasks and highlight their psychometric benefits over neuropsychological measures. Based on these results, we discuss the need to bridge the gap between clinical understanding of putative mechanisms underlying memory disorders and neuroscientific findings obtained using lab-based free recall tasks.

Physical transport processes such as the circulation and mixing of waters largely determine the spatial distribution of materials in the ocean. They also establish the physical environment within which biogeochemical and other processes transform materials, including naturally occurring nutrients and human-made contaminants that may sustain or harm the region’s living resources. Thus, understanding and modeling the transport and distribution of materials provides a crucial substrate for determining the effects of biological, geological, and chemical processes. The wide range of scales in which these physical processes operate includes microscale droplets and bubbles; small-scale turbulence in buoyant plumes and the near-surface “mixed” layer; submesoscale fronts, convergent and divergent flows, and small eddies; larger mesoscale quasi-geostrophic eddies; and the overall large-scale circulation of the Gulf of Mexico and its interaction with the Atlantic Ocean and the Caribbean Sea; along with air-sea interaction on longer timescales. The circulation and mixing processes that operate near the Gulf of Mexico coasts, where most human activities occur, are strongly affected by wind- and river-induced currents and are further modified by the area’s complex topography. Gulf of Mexico physical processes are also characterized by strong linkages between coastal/shelf and deeper offshore waters that determine connectivity to the basin’s interior. This physical connectivity influences the transport of materials among different coastal areas within the Gulf of Mexico and can extend to adjacent basins. Major advances enabled by the Gulf of Mexico Research Initiative in the observation, understanding, and modeling of all of these aspects of the Gulf’s physical environment are summarized in this article, and key priorities for future work are also identified.

The Gulf of Mexico Research Initiative (GoMRI) program funded research for 10 years following the Deepwater Horizon incident to address five themes, one of which was technology developments for improved response, mitigation, detection, characterization, and remediation associated with oil spills and gas releases. This paper features a sampling of such developments or advancements, most of which cite studies funded by GoMRI, but we also include several developments that occurred outside this program. We provide descriptions of new techniques or the novel application or enhancement of existing techniques related to studies on the evolution of the subsurface oil plume, the collection of data on ocean currents to support oil transport modeling, and oil spill modeling. We also feature developments related to the interactions of oil with particulate matter and microbial organisms, sampling for studies and analysis of biogeochemical processes related to oil fate, human health risks from inhalation of oil spill chemicals, impacts on marine life, and alternative dispersant technologies to Corexit®. Many of the techniques featured here have contributed to complementary or subsequent research and have applications beyond oil spill research that can contribute to a wide range of scientific endeavors.

Although recall proceeds most naturally in the order of encoding, people can recall items in reverse order. Prior studies ask whether and how forward and backward recall differ. We reexamine this classic question by studying recall dynamics while varying the predictability and timing of forward and backward cues. Although overall accuracy did not differ by recall direction, recall dynamics highlight key distinctions. Forward recall exhibits a modest advantage for correct transitions following errors, independent of cuing predictability and list length. Without consistent directional cuing, participants initiate backward recall more accurately, but this effect reverses with predictable directional cues. Following omissions, participants commit more fill-in errors in backward recall. Our findings implicate an asymmetric, cue-dependent retrieval process underlying forward and backward recall, with relative contributions of primacy and recency depending on directional predictability.

Antimicrobial resistance could cause 10 million deaths per year by 2050 if no action is taken. While we depend on researchers to find new antimicrobials, reducing the demand for existing ones requires human behaviour change. This article by The Behavioural Insights Team discusses some of the areas with the greatest potential for behavioural interventions to reduce the development of antimicrobial resistance. Three areas are discussed: (i) ‘nudging’ antimicrobial stewardship (e.g. highlighting comparative over-prescribing was seen to reduce GP antibiotics prescriptions by 3.3%); (ii) promoting good hygiene practices (e.g. placement and salience of hand sanitizer increased hospital visitor compliance from 0.4% to 19.7%); and (iii) leveraging market forces (e.g. front-of-package labelling could increase demand for meat produced with minimal antibiotics, encouraging food production behaviour change).

Lipids are essential components of bacterial membranes and phages are quasi-ubiquitous in bacteria. In the human pathogenStaphylococcus aureus, two common prophages ϕ13 and ϕ11.1 are preferentially integrated in lipase genes, and act as regulatory switches of respectively Geh, a triglyceride lipase, and Hlb, a sphingomyelinase. The factors driving selection for this prophage conservation in lipase genes and the impact onS. aureusfitness are not well understood. We report that prophage status of both ϕ13 and ϕ11.1 affect membrane phospholipid composition and bacterial growth in serum. They vary the extent to which toxic C18:2, released from Geh activity on triglycerides, are incorporated in bacterial membranes. Hlb and Geh lipases lead respectively to palmitic acid C16 and linoleic acid C18:2, which compete for binding to fatty acid kinase subunit FakB1. When both lipases are active, interference from C16 decreases C18:2 incorporationviaFakB1 and reduces fatty acid synthesis (FASII)-mediated elongation. In the presence of FASII inhibitor AFN-1252,S. aureusrelies on exogenous fatty acids, and adapts faster when Hlb is intact (ϕ13 absent), but slower when Hlb is inhibited. Faster adaptation correlates with less incorporation of C18:2. These findings contribute to explaining the selective advantage of Hlb-conversion by ϕ13 as a means of increasing membrane plasticity andS. aureusadaptation to environmental lipids. They also reveal an effect of ϕ13 status on anti-FASII adaptation. Prophage status and host-specific lipid environments may be important for accurate prediction ofS. aureusinfection risk and efficacy of new therapeutics.ImportanceStaphylococcus aureusis a major cause of untreatable human bacterial infections and its lipases are crucial for virulence and immune response escape. Prophages inserted in these lipase-encoding genes able to reversibly switch their activities are common inS. aureus, but the selective benefits of their maintenance is little understood. We demonstrate that two prophages, inserted in triglyceride and sphingomyelin lipase genes, interactively modulate fatty acid incorporation into bacterial membranes. The presence or absence of these prophages determine howS. aureusadapts to lipid environments, by affecting membrane plasticity, bacterial fitness, and adaptation to an antibiotic inhibiting fatty acid synthesis. Our findings highlight the importance of assessingS. aureusprophages and host lipid environments when evaluating infection risk and therapy efficacy.

IMPORTANCE The use of artificial intelligence (AI) is accelerating in all aspects of medicine and has the potential to transform clinical care and dermatology workflows. However, to develop image-based algorithms for dermatology applications, comprehensive criteria establishing development and performance evaluation standards are required to ensure product fairness, reliability, and safety. OBJECTIVE To consolidate limited existing literature with expert opinion to guide developers and reviewers of dermatology AI. EVIDENCE REVIEW In this consensus statement, the 19 members of the International Skin Imaging Collaboration AI working group volunteered to provide a consensus statement. A systematic PubMed search was performed of English-language articles published between December 1, 2008, and August 24, 2021, for “artificial intelligence” and “reporting guidelines,” as well as other pertinent studies identified by the expert panel. Factors that were viewed as critical to AI development and performance evaluation were included and underwent 2 rounds of electronic discussion to achieve consensus. FINDINGS A checklist of items was developed that outlines best practices of image-based AI development and assessment in dermatology. CONCLUSIONS AND RELEVANCE Clinically effective AI needs to be fair, reliable, and safe; this checklist of best practices will help both developers and reviewers achieve this goal.

We study a conceivable two-fluid system with a layer of one fluid between a solid support and a semi-infinite layer of the other fluid in which the molecular van der Waals (vdW) forces act like gravity in well-studied cases with similar spatial arrangements. The solid support consists of two layers so that vdW forces are, similar to the gravity systems (GS), finite at the solid–fluid interface. In this Part 1, we focus on the Young–Laplace (YL) equilibrium drops of the “light” liquid with a zero angle between the solid–fluid and fluid–fluid interfaces and compare them with the YL drops in the analogous GS. We point out that there is essentially just a single GS, in contrast to a continuum of vdW systems corresponding to different values of a dimensionless Hamaker constant (DHC). We find that when the latter is above a certain threshold value, the YL drop volume cannot exceed a certain terminal value, just as it is known to be the case for GS. In contrast, in vdW systems with the smaller DHC, the YL drops may have arbitrarily large volumes, which is a major difference from GS. We introduce a certain “non-classical particle” kinetic energy and a corresponding generalized phase plane. These “energy” considerations predict interfaces with vertical tangents, which are in an excellent agreement with equilibrium drop interfaces found by numerical continuation methods. For small DHC, numerical simulations on a neutral-wave-long interval confirm the lubrication-approximation evolutions from initially flat films toward the—perpetually approached—equilibrium YL drops of the same volume. We point out that the evolution for larger DHC may be approached by the boundary integral methods suitable for the Stokes flows, which we will further investigate in the future Part 2 of this work.

The joint effects of an insoluble surfactant and gravity on the linear stability of a two-layer Couette flow in a horizontal channel are investigated. The inertialess instability regimes are studied for arbitrary wavelengths and with no simplifying requirements on the system parameters: the ratio of thicknesses of the two fluid layers; the viscosity ratio; the base shear rate; the Marangoni number $Ma$; and the Bond number $Bo$. As was established in the first part of this investigation (Frenkel, Halpern & Schweiger, J. Fluid Mech., vol. 863, 2019, pp. 150–184), a quadratic dispersion equation for the complex growth rate yields two, largely continuous, branches of the normal modes, which are responsible for the flow stability properties. This is consistent with the surfactant instability case of zero gravity studied in Halpern & Frenkel (J. Fluid Mech., vol. 485, 2003, pp. 191–220). The present paper focuses on the mid-wave regimes of instability, defined as those having a finite interval of unstable wavenumbers bounded away from zero. In particular, the location of the mid-wave instability regions in the ($Ma$, $Bo$)-plane, bounded by their critical curves, depending on the other system parameters, is considered. The changes of the extremal points of these critical curves with the variation of external parameters are investigated, including the bifurcation points at which new extrema emerge. Also, it is found that for the less unstable branch of normal modes, a mid-wave interval of unstable wavenumbers may sometimes coexist with a long-wave one, defined as an interval having a zero-wavenumber endpoint.

A linear stability analysis of a two-layer plane Couette flow of two immiscible fluid layers with different densities, viscosities and thicknesses, bounded by two infinite parallel plates moving at a constant relative velocity to each other, with an insoluble surfactant monolayer along the interface and in the presence of gravity is carried out. The normal modes approach is applied to the equations governing flow disturbances in the two layers. These equations, together with boundary conditions at the plates and the interface, yield a linear eigenvalue problem. When inertia is neglected the velocity amplitudes are the linear combinations of certain hyperbolic functions, and a quadratic dispersion equation for the increment, that is the complex growth rate, is obtained, where coefficients depend on the aspect ratio, the viscosity ratio, the basic velocity shear, the Marangoni number $Ma$ that measures the effects of surfactant and the Bond number $Bo$ that measures the influence of gravity. An extensive investigation is carried out that examines the stabilizing or destabilizing influences of these parameters. Since the dispersion equation is quadratic in the growth rate, there are two continuous branches of the normal modes: a robust branch that exists even with no surfactant, and a surfactant branch that, to the contrary, vanishes when $Ma\downarrow 0$. Regimes have been uncovered with crossings of the two dispersion curves, their reconnections at the point of crossing and separations as $Bo$ changes. Due to the availability of the explicit forms for the growth rates, in many instances the numerical results are corroborated with analytical asymptotics.

Aerobic bacteria are frequent primocolonizers of the human naive intestine. Their generally accepted role is to eliminate oxygen, which would allow colonization by anaerobes that subsequently dominate bacterial gut populations., Aerobic bacteria are frequent primocolonizers of the human naive intestine. Their generally accepted role is to eliminate oxygen, which would allow colonization by anaerobes that subsequently dominate bacterial gut populations. In this hypothesis-based study, we revisited this dogma experimentally in a germfree mouse model as a mimic of the germfree newborn. We varied conditions leading to the establishment of the dominant intestinal anaerobe Bacteroides thetaiotaomicron. Two variables were introduced: Bacteroides inoculum size and preestablishment by bacteria capable or not of consuming oxygen. High Bacteroides inoculum size enabled its primocolonization. At low inocula, we show that bacterial preestablishment was decisive for subsequent Bacteroides colonization. However, even non-oxygen-respiring bacteria, a hemA Escherichia coli mutant and the intestinal obligate anaerobe Clostridium scindens, facilitated Bacteroides establishment. These findings, which are supported by recent reports, revise the long-held assumption that oxygen scavenging is the main role for aerobic primocolonizing bacteria. Instead, we suggest that better survival of aerobic bacteria ex vivo during vectorization between hosts could be a reason for their frequent primocolonization.

Political partisans see the world through an ideologically biased lens. What drives political polarization? Although it has been posited that polarization arises because of an inability to tolerate uncertainty and a need to hold predictable beliefs about the world, evidence for this hypothesis remains elusive. We examined the relationship between uncertainty tolerance and political polarization using a combination of brain-to-brain synchrony and intersubject representational similarity analysis, which measured committed liberals’ and conservatives’ (n = 44) subjective interpretation of naturalistic political video material. Shared ideology between participants increased neural synchrony throughout the brain during a polarizing political debate filled with provocative language but not during a neutrally worded news clip on polarized topics or a nonpolitical documentary. During the political debate, neural synchrony in mentalizing and valuation networks was modulated by one’s aversion to uncertainty: Uncertainty-intolerant individuals experienced greater brain-to-brain synchrony with politically like-minded peers and lower synchrony with political opponents—an effect observed for liberals and conservatives alike. Moreover, the greater the neural synchrony between committed partisans, the more likely that two individuals formed similar, polarized attitudes about the debate. These results suggest that uncertainty attitudes gate the shared neural processing of political narratives, thereby fueling polarized attitude formation about hot-button issues.

In recent years, the cognitive neuroscience literature has come under criticism for containing many low-powered studies, limiting the ability to make reliable statistical inferences. Typically, the suggestion for increasing power is to collect more data with neural signals. However, many studies in cognitive neuroscience use parameters estimated from behavioral data in order to make inferences about neural signals (such as fMRI BOLD signal). In this paper, we explore how cognitive neuroscientists can learn more about their neuroimaging signal by collecting data on behavior alone. We demonstrate through simulation that knowing more about the marginal distribution of behavioral parameters can improve inferences about the mapping between cognitive processes and neural data. In realistic settings of the correlation between cognitive and neural parameters, additional behavioral data can lead to the same improvement in the precision of inferences more cheaply and easily than collecting additional data from subjects in a neuroimaging study. This means that when conducting an neuroimaging study, researchers now have two knobs to turn in a design analysis: the number of subjects collected in the scanner and the number of behavioral subjects collected outside the scanner (in the lab or online).

Political partisans see the world through an ideologically biased lens. What drives political polarization? It has been posited that polarization arises because holding extreme political views satisfies a need for certain and stable beliefs about the world. We examined the relationship between uncertainty tolerance and political polarization using brain-to-brain synchrony analysis, which measured committed liberals’ and conservatives’ subjective interpretation of a continuous political narrative. Participants (N=44) watched a political debate while undergoing fMRI. Shared ideology between participants increased neural synchrony in many brain areas including key regions of the valuation and theory-of-mind networks (e.g. temporoparietal junction). The degree of neural synchrony was modulated by uncertainty aversion: Uncertainty-intolerant individuals experienced greater brain-to-brain synchrony with politically like-minded peers and lower synchrony with political opponents. This effect was observed for liberals and conservatives alike. Moreover, increasing neural synchrony between committed partisans predicted subsequent polarized attitude formation about the debate after the scanning session. These results suggest that uncertainty attitudes gate the shared neural processing of political narratives, thereby fueling polarized attitude formation about hot-button issues.

Flavobacterium psychrophilum causes bacterial cold-water disease in wild and aquaculture-reared fish and is a major problem for salmonid aquaculture. The mechanisms responsible for cold-water disease are not known. It was recently demonstrated that the related fish pathogen, Flavobacterium columnare, requires a functional type IX protein secretion system (T9SS) to cause disease. T9SSs secrete cell surface adhesins, gliding motility proteins, peptidases, and other enzymes, any of which may be virulence factors. The F. psychrophilum genome has genes predicted to encode components of a T9SS. Here, we used a SacB-mediated gene deletion technique recently adapted for use in the Bacteroidetes to delete a core F. psychrophilum T9SS gene, gldN. The ΔgldN mutant cells were deficient for secretion of many proteins in comparison to wild-type cells. Complementation of the mutant with wild-type gldN on a plasmid restored secretion. Compared to wild-type and complemented strains, the ΔgldN mutant was deficient in adhesion, gliding motility, and extracellular proteolytic and hemolytic activities. The ΔgldN mutant exhibited reduced virulence in rainbow trout and complementation restored virulence, suggesting that the T9SS plays an important role in the disease. IMPORTANCE Bacterial cold-water disease, caused by F. psychrophilum, is a major problem for salmonid aquaculture. Little is known regarding the virulence factors involved in this disease, and control measures are inadequate. A targeted gene deletion method was adapted to F. psychrophilum and used to demonstrate the importance of the T9SS in virulence. Proteins secreted by this system are likely virulence factors and targets for the development of control measures.

Fatty acid biosynthesis (FASII) enzymes are considered valid targets for antimicrobial drug development against the human pathogenStaphylococcus aureus. However, incorporation of host fatty acids confers FASII antibiotic adaptation that compromises prospective treatments.S. aureusadapts to FASII inhibitors by a first non-replicative latency period followed by outgrowth. Here we used transcriptional fusions and direct metabolite measurements to investigate the factors that dictate the duration of latency prior to outgrowth. We show that stringent response induction leads to repression of FASII and phospholipid synthesis genes. (p)ppGpp induction inhibits synthesis of malonyl-CoA, a molecule that derepresses FapR, a key regulator of FASII and phospholipid synthesis. Anti-FASII treatment also triggers transient expression of (p)ppGpp-regulated genes during the anti-FASII latency phase, with concomitant repression of FapR regulon expression. These effects are reversed upon outgrowth. GTP depletion, a known consequence of stringent response, also occurs during FASII latency, and is proposed as the common signal linking these responses. We next show that anti-FASII treatment shifts malonyl-CoA distribution between its interactants FapR and FabD, towards FapR, increasing expression of phospholipid synthesis genesplsXandplsCduring outgrowth. We conclude that components of the stringent response dictate malonyl-CoA availability inS. aureusFASII regulation, and contribute to latency prior to anti-FASII-adapted outgrowth. A combinatory approach, coupling a (p)ppGpp inducer and an anti-FASII, blocksS. aureusoutgrowth, opening perspectives for bi-therapy treatment.ImportanceStaphylococcus aureusis a major human bacterial pathogen for which new inhibitors are urgently needed. Antibiotic development has centered on the fatty acid synthesis (FASII) pathway, which provides the building blocks for bacterial membrane phospholipids. However,S. aureusovercomes FASII inhibition and adapts to anti-FASII by using exogenous fatty acids that are abundant in host environments. This adaptation mechanism comprises a transient latency period, followed by bacterial outgrowth. Here we use metabolite sensors and promoter reporters to show that responses to stringent conditions and to FASII inhibition intersect: both involve GTP and malonyl-CoA. These two signaling molecules contribute to modulating the duration of latency prior toS. aureusadaptation outgrowth. We exploit these novel findings to propose a bi-therapy treatment against staphylococcal infections.

ALMA (Anti-symmetric, Large-Moment, Accelerated) is a fast, flexible, and scalable toolkit designed to solve hyperbolic conservation law systems in hybrid supercomputers. This manuscript describes the theoretical background and implementation of ALMA , which uses the anti-symmetric formulation of fluids to obtain simple, robust, and easily paralellizable code. Practical GPU acceleration is realized on entire applications with an overall gain factor of 2 to 4. ALMA also provides a parallel, GPU accelerated sparse solver based on geometric multigrid, capable of diagonalizing linear systems with 239 unknowns. We demonstrate ALMA 's scaling and performance in petascale supercomputers and use standard fluid models to verify the overall approach with canonical benchmark problems.

A horizontal channel flow of two immiscible fluid layers with different densities, viscosities and thicknesses, subject to vertical gravitational forces and with an insoluble surfactant monolayer present at the interface, is investigated. The base Couette flow is driven by the uniform horizontal motion of the channel walls. Linear and nonlinear stages of the (inertialess) surfactant and gravity dependent long-wave instability are studied using the lubrication approximation, which leads to a system of coupled nonlinear evolution equations for the interface and surfactant disturbances. The (inertialess) instability is a combined result of the surfactant action characterized by the Marangoni number $Ma$ and the gravitational effect corresponding to the Bond number $Bo$ that ranges from $-\infty$ to $\infty$. The other parameters are the top-to-bottom thickness ratio $n$, which is restricted to $n\geqslant 1$ by a reference frame choice, the top-to-bottom viscosity ratio $m$ and the base shear rate $s$. The linear stability is determined by an eigenvalue problem for the normal modes, where the complex eigenvalues (determining growth rates and phase velocities) and eigenfunctions (the amplitudes of disturbances of the interface, surfactant, velocities and pressures) are found analytically by using the smallness of the wavenumber. For each wavenumber, there are two active normal modes, called the surfactant and the robust modes. The robust mode is unstable when $Bo/Ma$ falls below a certain value dependent on $m$ and $n$. The surfactant branch has instability for $m, and any $Bo$, although the range of unstable wavenumbers decreases as the stabilizing effect of gravity represented by $Bo$ increases. Thus, for certain parametric ranges, even arbitrarily strong gravity cannot completely stabilize the flow. The correlations of vorticity-thickness phase differences with instability, present when gravitational effects are neglected, are found to break down when gravity is important. The physical mechanisms of instability for the two modes are explained with vorticity playing no role in them. This is in marked contrast to the dynamical role of vorticity in the mechanism of the well-known Yih instability due to effects of inertia, and is contrary to some earlier literature. Unlike the semi-infinite case that we previously studied, a small-amplitude saturation of the surfactant instability is possible in the absence of gravity. For certain $(m,n)$-ranges, the interface deflection is governed by a decoupled Kuramoto–Sivashinsky equation, which provides a source term for a linear convection–diffusion equation governing the surfactant concentration. When the diffusion term is negligible, this surfactant equation has an analytic solution which is consistent with the full numerics. Just like the interface, the surfactant wave is chaotic, but the ratio of the two waves turns out to be constant.

For a liquid film falling down along a vertical fibre, classical theory (Kalliadasis & Chang J. Fluid Mech., vol. 261, 1994, pp. 135–168; Yu & Hinch J. Fluid Mech., vol. 737, 2013, pp. 232–248) showed that drop formation can occur due to capillary instability when the Bond number $G=\unicode[STIX]{x1D70C}ga^{3}/\unicode[STIX]{x1D6FE}h_{0}$ is below the critical value $G_{c}\approx 0.60$, where $\unicode[STIX]{x1D70C}$ is the fluid density, $g$ is the gravitational acceleration, $a$ is the fibre radius, $\unicode[STIX]{x1D6FE}$ is the surface tension and $h_{0}$ is the unperturbed film thickness. However, the experiment by Quéré (Europhys. Lett., vol. 13 (8), 1990, pp. 721–726) found $G_{c}\approx 0.71$, which is slightly greater than the above theoretical value. Here we offer a plausible way to resolve this discrepancy by including additional wall slip whose amount can be measured by the slip parameter $\unicode[STIX]{x1D6EC}=3\unicode[STIX]{x1D706}/h_{0}$, where $\unicode[STIX]{x1D706}$ is the slip length. Using lubrication theory, we find that wall slip promotes capillary instability and, hence, enhances drop formation. In particular, when slip effects are strong ($\unicode[STIX]{x1D6EC}\gg 1$), the transition films and the drop height scale as $(c/\unicode[STIX]{x1D6EC})^{-1/3}$ and $(c/\unicode[STIX]{x1D6EC})^{2/3}$, respectively, distinct from those found by Yu & Hinch for the no-slip case where $c$ is the travelling speed. In addition, for $\unicode[STIX]{x1D6EC}>1$, $G_{c}$ is found to increase with $\unicode[STIX]{x1D6EC}$ according to $G_{c}\approx 0.7\unicode[STIX]{x1D6EC}^{1/3}$, offering a possible explanation why the $G_{c}$ found by Quéré is slightly greater than that predicted by the no-slip model. Using the above expression, the estimated slip length in Quéré’s experiment is found to be of the order of several micrometres, consistent with the typical slip length range 1–$10~\unicode[STIX]{x03BC}\text{m}$ for polymeric liquids such as silicone oil used in his experiment. The existence of wall slip in Quéré’s experiment is further supported by the observation that the film thinning kinetics exhibits the no-slip result $h\propto t^{-1/2}$ for early times and changes to the strong slip result $h\propto t^{-1}$, where $h$ is the film thickness. We also show that when the film is ultrathin, although capillary instability can become further amplified by strong slip effects, the instability can be arrested by the equally intensified gravity draining in the weakly nonlinear regime whose dynamics is governed by the Kuramoto–Sivashinsky equation.

Intervening on causal systems can illuminate their underlying structures. Past work has shown that, relative to adults, young children often make intervention decisions that appear to confirm a single hypothesis rather than those that optimally discriminate alternative hypotheses. Here, we investigated how the ability to make informative causal interventions changes across development. Ninety participants between the ages of 7 and 25 completed 40 different puzzles in which they had to intervene on various causal systems to determine their underlying structures. Each puzzle comprised a three- or four-node computer chip with hidden wires. On each trial, participants viewed two possible arrangements of the chip's hidden wires and had to select a single node to activate. After observing the outcome of their intervention, participants selected a wire configuration and rated their confidence in their selection. We characterized participant choices with a Bayesian measurement model that indexed the extent to which participants selected nodes that would best disambiguate the two possible causal structures versus those that had high causal centrality in one of the two causal hypotheses but did not necessarily discriminate between them. Our model estimates revealed that the use of a discriminatory strategy increased through early adolescence. Further, developmental improvements in intervention strategy were related to changes in the ability to accurately judge the strength of evidence that interventions revealed, as indexed by participants' confidence in their selections. Our results suggest that improvements in causal information-seeking extend into adolescence and may be driven by metacognitive sensitivity to the efficacy of previous interventions in discriminating competing ideas.

SummaryDevelopment of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for anti-FASII efficacy in animal models supported this view. However, restricted test conditions used previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, leading to increased retention of the two substrates required for exogenous fatty acid (eFA) utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the postulate of fatty acid stringency, and reveals an Achilles’ heel for using FASII antibiotics to treat infection in monotherapy.Significance statementAntibiotic discovery to overcome treatment failure has huge socio-medical and economic stakes. The fatty acid synthesis (FASII) pathway is considered an ideal druggable target against the human pathogen Staphylococcus aureus, based on evidence of anti-FASII efficacy in infection models, and the postulate that S. aureus synthesizes an irreplaceable fatty acid. We report that S. aureus alters its behavior in host-relevant conditions. Administering FASII antibiotics upon signs of infection, rather than just after inoculation as frequently practiced, failed to clear septicemic infections. In serum, S. aureus rapidly overcomes FASII antibiotics by incorporating alternative fatty acids. We conclude that previously, premature antibiotic treatments and experimental constraints masked S. aureus antibiotic adaptation capacity. These findings should help streamline future drug development programs.