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In 1872, Maxwell proposed his famous ‘demon’ thought experiment 1 . By discerning which particles in a gas are hot and which are cold, and then performing a series of reversible actions, Maxwell’s demon could rearrange the particles into a manifestly lower-entropy state. This apparent violation of the second law of thermodynamics was resolved by twentieth-century theoretical work 2 : the entropy of the Universe is often increased while gathering information 3 , and there is an unavoidable entropy increase associated with the demon’s memory 4 . The appeal of the thought experiment has led many real experiments to be framed as demon-like. However, past experiments had no intermediate information storage 5 , yielded only a small change in the system entropy 6 , 7 or involved systems of four or fewer particles 8 – 10 . Here we present an experiment that captures the full essence of Maxwell’s thought experiment. We start with a randomly half-filled three-dimensional optical lattice with about 60 atoms. We make the atoms sufficiently vibrationally cold so that the initial disorder is the dominant entropy. After determining where the atoms are, we execute a series of reversible operations to create a fully filled sublattice, which is a manifestly low-entropy state. Our sorting process lowers the total entropy of the system by a factor of 2.44. This highly filled ultracold array could be used as the starting point for a neutral-atom quantum computer. An experiment inspired by Maxwell’s ‘demon’ thought experiment uses a series of reversible operations to fully fill a three-dimensional optical lattice with ultracold atoms and realize a low-entropy state.

About the Authors: Victor I. Band Affiliations Emory Antibiotic Resistance Center, Emory University, Atlanta, Georgia, United States of America, Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America David S. Weiss * E-mail: david.weiss@emory.edu Affiliations Emory Antibiotic Resistance Center, Emory University, Atlanta, Georgia, United States of America, Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America ORCID logo http://orcid.org/0000-0003-0980-7866 Citation: Band VI, Weiss DS (2019) Heteroresistance: A cause of unexplained antibiotic treatment failure? According to the Centers for Disease Control and Prevention (CDC), over 2 million infections every year in the United States are caused by antibiotic-resistant bacteria, resulting in at least 23,000 deaths and US$55 billion in increased healthcare costs and lost productivity [1]. [...]even when a bacterial isolate is classified as susceptible to a given antibiotic, it is expected that antibiotic therapy will fail 10% of the time [26]. [...]the burden of such unexplained treatment failures is significant, and HR is a possible cause. Some cancers have been observed to harbor a small population of phenotypically resistant cells exhibiting chromatin modifications, allowing the cells to resist 500-times-greater concentrations of chemotherapeutic tyrosine kinase inhibitors [31]. [...]HR or similar phenomena may explain the resistance of some cancers to chemotherapeutics when the majority of the tumor cells appear to respond to therapy.

Although the quality of individual quantum bits (qubits) and quantum gates has been steadily improving, the number of qubits in a single system has increased quite slowly. Here, we demonstrate arbitrary single-qubit gates based on targeted phase shifts, an approach that can be applied to atom, ion, or other atom-like systems. These gates are highly insensitive to addressing beam imperfections and have little cross-talk, allowing for a dramatic scaling up of qubit number. We have performed gates in series on 48 individually targeted sites in a 40% full 5 by 5 by 5 three-dimensional array created by an optical lattice. Using randomized benchmarking, we demonstrate an average gate fidelity of 0.9962(16), with an average cross-talk fidelity of 0.9979(2) (numbers in parentheses indicate the one standard deviation uncertainty in the final digits).

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation and that when this occurs, all the cells in the bacterial population are phenotypically resistant. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we provide evidence that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by resistance. This suggests the possibility that HR may often develop before resistance and frequently be a stage in its progression, potentially representing a major shift in our understanding of the evolution of antibiotic resistance.

Significance The clustered, regularly interspaced, short palindromic repeats associated endonuclease, Cas9, has quickly become a revolutionary tool in genome engineering. Utilizing small guiding RNAs, Cas9 can be targeted to specific DNA sequences of interest, where it catalyzes DNA cleavage. We now demonstrate that Cas9 from the Gram-negative bacterium Francisella novicida (FnCas9) can be reprogrammed to target a specific RNA substrate, the genome of the +ssRNA virus, hepatitis C virus, in eukaryotic cells. Further, this targeting results in inhibition of viral protein production. Overall, programmable Cas9-mediated viral RNA targeting likely represents one of myriad potential applications of FnCas9 in RNA targeting in eukaryotic cells. Clustered, regularly interspaced, short palindromic repeats–CRISPR associated (CRISPR-Cas) systems are prokaryotic RNA-directed endonuclease machineries that act as an adaptive immune system against foreign genetic elements. Using small CRISPR RNAs that provide specificity, Cas proteins recognize and degrade nucleic acids. Our previous work demonstrated that the Cas9 endonuclease from Francisella novicida (FnCas9) is capable of targeting endogenous bacterial RNA. Here, we show that FnCas9 can be directed by an engineered RNA-targeting guide RNA to target and inhibit a human +ssRNA virus, hepatitis C virus, within eukaryotic cells. This work reveals a versatile and portable RNA-targeting system that can effectively function in eukaryotic cells and be programmed as an antiviral defense.

Bacterial SPOR domains bind peptidoglycan (PG) and are thought to target proteins to the cell division site by binding to “denuded” glycan strands that lack stem peptides, but uncertainties remain, in part because septal-specific binding has yet to be studied in a purified system. Here we show that fusions of GFP to SPOR domains from theEscherichia colicell-division proteins DamX, DedD, FtsN, and RlpA all localize to septal regions of purified PG sacculi obtained fromE. coliandBacillus subtilis. Treatment of sacculi with an amidase that removes stem peptides enhanced SPOR domain binding, whereas treatment with a lytic transglycosylase that removes denuded glycans reduced SPOR domain binding. These findings demonstrate unequivocally that SPOR domains localize by binding to septal PG, that the physiologically relevant binding site is indeed a denuded glycan, and that denuded glycans are enriched in septal PG rather than distributed uniformly around the sacculus. Accumulation of denuded glycans in the septal PG of bothE. coliandB. subtilis, organisms separated by 1 billion years of evolution, suggests that sequential removal of stem peptides followed by degradation of the glycan backbone is an ancient feature of PG turnover during bacterial cell division. Linking SPOR domain localization to the abundance of a structure (denuded glycans) present only transiently during biogenesis of septal PG provides a mechanism for coordinating the function of SPOR domain proteins with the progress of cell division.

We report the observation of a one-dimensional (1D) Tonks-Girardeau (TG) gas of bosons moving freely in 1D. Although TG gas bosons are strongly interacting, they behave very much like noninteracting fermions. We enter the TG regime with cold rubidium-87 atoms by trapping them with a combination of two light traps. By changing the trap intensities, and hence the atomic interaction strength, the atoms can be made to act either like a Bose-Einstein condensate or like a TG gas. We measure the total 1D energy and the length of the gas. With no free parameters and over a wide range of coupling strengths, our data fit the exact solution for the ground state of a 1D Bose gas.

FtsN plays an essential role in promoting the inward synthesis of septal peptidoglycan (sPG) by the FtsWI complex during bacterial cell division. How it achieves this role is unclear. Here we use single-molecule tracking to investigate FtsN’s dynamics during sPG synthesis in E. coli . We show that septal FtsN molecules move processively at ~9 nm s −1 , the same as FtsWI molecules engaged in sPG synthesis (termed sPG-track), but much slower than the ~30 nm s −1 speed of inactive FtsWI molecules coupled to FtsZ’s treadmilling dynamics (termed FtsZ-track). Importantly, processive movement of FtsN is exclusively coupled to sPG synthesis and is required to maintain active sPG synthesis by FtsWI. Our findings indicate that FtsN is part of the FtsWI sPG synthesis complex, and that while FtsN is often described as a “trigger” for the initiation for cell wall constriction, it must remain part of the processive FtsWI complex to maintain sPG synthesis activity. FtsN promotes the inward synthesis of septal peptidoglycan (sPG) through the FtsWI complex during bacterial cell division. Here, Lyu et al. apply single-molecule microscopy on E. coli to show that FtsN proteins (I) move processively at a speed similar to that of FtsWI molecules. (II) can be divided into two populations based on their speeds, and (III) their movement is driven exclusively by peptidoglycan synthesis

The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8⁺ T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4⁺ and CD8⁺ T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.

Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including carbapenem-resistant Klebsiella pneumoniae (CRKP), which lead to mortality rates as high as 40 to 50%. Few treatment options are available to treat CRKP, and the polymyxin antibiotic colistin is often the “last-line” therapy. However, resistance to colistin is increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates that were classified as susceptible to colistin by clinical diagnostics yet harbored a minor subpopulation of phenotypically resistant cells. Within these isolates, the resistant subpopulation became predominant after growth in the presence of colistin but returned to baseline levels after subsequent culture in antibiotic-free media. This indicates that the resistance was phenotypic, rather than due to a genetic mutation, consistent with heteroresistance. Importantly, colistin therapy was unable to rescue mice infected with the heteroresistant strains. These findings demonstrate that colistin heteroresistance may cause in vivo treatment failure during K. pneumoniae infection, threatening the use of colistin as a last-line treatment for CRKP. Furthermore, these data sound the alarm for use of caution in interpreting colistin susceptibility test results, as isolates identified as susceptible may in fact resist antibiotic therapy and lead to unexplained treatment failures. IMPORTANCE This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics. This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics.