BINA

We present a detailed description of the experiment realizing for the first time a protective measurement, a novel measurement protocol which combines weak interactions with a “protection mechanism” preserving the measured state coherence during the whole measurement process. Furthermore, protective measurement allows finding the expectation value of an observable, ie, an inherently statistical quantity, by measuring a single particle, without the need for any statistics. This peculiar property, in sharp contrast to the framework of traditional (projective) quantum measurement, might constitute a groundbreaking advance for several quantum technology related fields. View Full-Text

The need for tissue contact makes photoacoustic imaging not applicable for special medical applications like wound imaging, endoscopy, or laser surgery. An easy, stable, and contact-free sensing technique might thus help to broaden the applications of the medical imaging modality. In this work, it is demonstrated for the first time that remote photoacoustic sensing by speckle analysis can be performed in the MHz sampling range by tracking a single speckle using a four quadrant photo-detector. A single speckle, which is created by self-interference of surface back-reflection, is temporally analyzed using this photo-detector. Phantoms and skin samples are measured in transmission and reflection mode. The potential for miniaturization for endoscopic application is demonstrated by fiber bundle measurements. In addition, sensing parameters are discussed. Photoacoustic sensing in the MHz sampling range by single speckle analysis with the four quadrant detector is successfully demonstrated. Furthermore, the endoscopic applicability is proven, and the sensing parameters are convenient for photoacoustic sensing. It can be concluded that a single speckle contains all the relevant information for remote photoacoustic signal detection. Single speckle sensing is therefore an easy, robust, contact-free photoacoustic detection technique and holds the potential for economical, ultra-fast photoacoustic sensing. The new detection technique might thus help to broaden the field of photoacoustic imaging applications in the future. View Full-Text

Thirty-five thousand people die as a result of more than 2.8 million antibiotic-resistant infections in the United States of America per year. Pseudomonas aeruginosa (P. aeruginosa) is classified a serious threat, the second-highest threat category of the US Department of Health and Human Services. Among others, the World Health Organization (WHO) encourages the discovery and development of novel antibiotic classes with new targets and mechanisms of action without cross-resistance to existing classes. To find potential new target sites in pathogenic bacteria, such as P. aeruginosa, it is inevitable to fully understand the molecular mechanism of homeostasis, metabolism, regulation, growth, and resistances thereof. P. aeruginosa maintains a sophisticated copper defense cascade comprising three stages, resembling those of public safety organizations. These stages include copper scavenging, first responder, and second responder. Similar mechanisms are found in numerous pathogens. Here we compare the copper-dependent transcription regulators cueR and copRS of Escherichia coli (E. coli) and P. aeruginosa. Further, phylogenetic analysis and structural modelling of mexPQ-opmE reveal that this efflux pump is unlikely to be involved in the copper export of P. aeruginosa. Altogether, we present current understandings of the copper homeostasis in P. aeruginosa and potential new target sites for antimicrobial agents or a combinatorial drug regimen in the fight against multidrug resistant pathogens. View Full-Text

Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells. We show that H358 cells devoid of Fer (H358ΔFer), strictly depend on glucose for their proliferation and growth, and fail to compensate for glucose withdrawal by oxidizing and metabolizing glutamine. Furthermore, glucose deficiency caused increased reactive oxygen species (ROS) production and induction of a DNA damage response (DDR), accompanied by the onset of apoptosis and attenuated cell-cycle progression. Analysis of mitochondrial function revealed impaired respiratory and electron transport chain (ETC) complex 1 (comp. I) activity in the Fer-deficient H358ΔFer cells. This was manifested by decreased levels of NAD+ and ATP and relatively low abundance of tricarboxylic acid (TCA) cycle metabolites. Impaired electron transport chain comp. I activity and dependence on glucose were also confirmed in Fer-deficient, MDA-MB-231ΔFer cells. Although both H358ΔFer and MDA-MB-231ΔFer cells showed a decreased aspartate level, this seemed to be compensated by the predominance of pyrimidines synthesis over the urea cycle progression. Notably, absence of Fer significantly impeded the growth of H358ΔFer and MDA-MB-231ΔFer xenografts in mice …

When cooled down, emulsion droplets stabilized by a frozen interface of alkane molecules and surfactants have been observed to undergo a spectacular sequence of morphological transformations: from spheres to faceted liquid icosahedra, down to flattened liquid platelets. While generally ascribed to the interplay between the elasticity of the frozen interface and surface tension, the physical mechanisms underpinning these transitions have remained elusive, despite different theoretical pictures having been proposed in recent years. In this Letter, we introduce a comprehensive mechanical model of morphing emulsion droplets, which quantitatively accounts for various experimental observations, including the size scaling behavior of the faceting transition. Our analysis highlights the role of gravity and the spontaneous curvature of the frozen interface in determining the specific transition pathway.

Inhibitor screening is an important tool for drug development, especially during the COVID-19 pandemic. The most used in vitro inhibitor screening tool is an enzyme-linked immunosorbent assay (ELISA). However, ELISA-based inhibitor screening is time consuming and has a limited dynamic range. Using fluorescently and magnetically modulated biosensors (MMB), we developed a rapid and sensitive inhibitor screening tool. This study demonstrates its performance by screening small molecules and neutralizing antibodies as potential inhibitors of the interaction between the spike protein 1 (S1) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the angiotensin-converting enzyme 2 (ACE2) receptor. The MMB-based assay is highly sensitive, has minimal non-specific binding, and is much faster than the commonly used ELISA (2 h vs. 7–24 h). We anticipate that our method will lead to a remarkable advance in screening for new drug candidates.

Near-infrared (NIR) fluorescence lifetime imaging (FLI) provides a unique contrast mechanism to monitor biological parameters and molecular events in vivo. Single-photon avalanche photodiode (SPAD) cameras have been recently demonstrated in FLI microscopy (FLIM) applications, but their suitability for in vivo macroscopic FLI (MFLI) in deep tissues remains to be demonstrated. Herein, we report in vivo NIR MFLI measurement with SwissSPAD2, a large time-gated SPAD camera. We first benchmark its performance in well-controlled in vitro experiments, ranging from monitoring environmental effects on fluorescence lifetime, to quantifying Förster Resonant Energy Transfer (FRET) between dyes. Next, we use it for in vivo studies of target-drug engagement in live and intact tumor xenografts using FRET. Information obtained with SwissSPAD2 was successfully compared to that obtained with a gated-ICCD camera, using two different approaches. Our results demonstrate that SPAD cameras offer a powerful technology for in vivo preclinical applications in the NIR window.

Absent pharmaceutical interventions, social distancing, lock-downs and mobility restrictions remain our prime response in the face of epidemic outbreaks. To ease their potentially devastating socioeconomic consequences, we propose here an alternating quarantine strategy: at every instance, half of the population remains under lockdown while the other half continues to be active-maintaining a routine of weekly succession between activity and quarantine. This regime minimizes infectious interactions, as it allows only half of the population to interact for just half of the time. As a result it provides a dramatic reduction in transmission, comparable to that achieved by a population-wide lockdown, despite sustaining socioeconomic continuity at~ 50% capacity. The weekly alternations also help address the specific challenge of COVID-19, as their periodicity synchronizes with the natural SARS-CoV-2 disease time-scales …

The purpose of this paper is to suggest frontier inter‐disciplinary research directions that can be considered as important horizons of modern electrochemistry in the field of energy storage and conversion. We selected several topics that call for advancements in solid‐state, interfacial, analytical and energy‐related electrochemical science. A dramatic improvement in the performance of energy storage and conversion devices is needed to meet the urgent demands of our society. Significantly more efficient devices are needed to meet two major challenges: electro‐mobility, namely electrochemical propulsion of electric vehicles, and the ability to store and convert large quantities of energy generated from sustainable sources such as sun and wind. We suggest promotion of breakthroughs in several important directions. The examples chosen include: Development of novel in‐situ methodologies for design and testing …

CRISPR-Cas9 is quickly revolutionizing the way we approach gene therapy. CRISPR-Cas9 is a complexed, two-component system using a short guide RNA (gRNA) sequence to direct the Cas9 endonuclease to the target site. Modifying the gRNA independent of the Cas9 protein confers ease and flexibility to improve the CRISPR-Cas9 system as a genome-editing tool. gRNAs have been engineered to improve the CRISPR system’s overall stability, specificity, safety, and versatility. gRNAs have been modified to increase their stability to guard against nuclease degradation, thereby enhancing their efficiency. Additionally, guide specificity has been improved by limiting off-target editing. Synthetic gRNA has been shown to ameliorate inflammatory signaling caused by the CRISPR system, thereby limiting immunogenicity and toxicity in edited mammalian cells. Furthermore, through conjugation with exogenous donor DNA, engineered gRNAs have been shown to improve homology-directed repair (HDR) efficiency by ensuring donor proximity to the edited site. Lastly, synthetic gRNAs attached to fluorescent labels have been developed to enable highly specific nuclear staining and imaging, enabling mechanistic studies of chromosomal dynamics and genomic mapping. Continued work on the modification and optimization of synthetic gRNAs will undoubtedly lead to clinical and therapeutic benefits and, ultimately, routinely performed CRISPR-based therapies.

In the parasite Trypanosoma brucei, the causative agent of human African sleeping sickness, all mRNAs are trans-spliced to generate a common 59 exon derived from the spliced leader RNA (SL RNA). Perturbations of protein translocation across the endoplasmic reticulum (ER) induce the spliced leader RNA silencing (SLS) pathway. SLS activation is mediated by a serine-threonine kinase, PK3, which translocates from the cytosolic face of the ER to the nucleus, where it phosphorylates the TATA binding protein TRF4, leading to the shut-off of SL RNA transcription, followed by induction of programmed cell death. Here, we demonstrate that SLS is also induced by depletion of the essential ER resident chaperones BiP and calreticulin, ER oxidoreductin 1 (ERO1), and the Golgi-localized quiescin sulfhydryl oxidase (QSOX1). Most strikingly, silencing of Rhomboid-like 1(TIMRHOM1) involved in mitochondrial protein import, also induces SLS. The PK3 kinase, which integrates SLS signals, is modified by phosphorylation on multiple sites. To determine which of the phosphorylation events activate PK3, several individual mutations or their combination were generated.These mutations failed to completely eliminate the phosphorylation or translocation of the kinase to the nucleus. The structure of PK3 kinase and its ATP binding domain were therefore modeled. A conserved phenylalanine at position 771 was proposed to interact with ATP, and the PK3F771L mutation completely eliminated phosphorylation under SLS, suggesting that the activation involves most if not all the phosphorylation sites. The study suggests that the SLS occurs broadly in …

Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we colonized gut organ cultures with longitudinal microbiota samples collected from newly-diagnosed and therapy-naive irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet, and reinforce the potential feasibility of microbiome based-therapies in IBS.

During embryonic development, mutually antagonistic signaling cascades determine the fate of the bipotential gonad towards a testicular or ovarian identity. Errors in this process result in human Disorders of Sex Development (DSDs), where there is discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in-vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells towards gonadal progenitors. Transcriptomic analysis reveals that the in-vitro-derived murine gonadal cells are equivalent to E11.5 in-vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete AMH, migrate and form tubular structures. The cells derived from a 46,XY DSD female hiPSCs, carrying a NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR/Cas9-mediated correction of the variant rescued the phenotype. This is a robust tool to understand mechanisms of sex-determination and model DSDs.

In highly polyandrous species, where females mate with multiple males within a single fertility period, there is typically a high level of sperm competition. To cope with this challenge, males apply various behavioral and physiological strategies to maximize their paternity rates. Previous studies in Drosophila melanogaster established a link between the composition of the social environment and the reproductive success of individual male flies. While most studies until now focused on the adaptive responses of male flies to the presence of rival males, little is known about whether the outcomes of sexual interactions with female partners affect male-male social interactions in a competitive environment such as the social group. Here we show that repeated failures to mate promote a coordinated physiological and behavioral responses that can serve to increase paternity chances over mating rivals. We exposed male flies to sexual deprivation or successful mating and analyzed the behavioral repertoires of individuals within groups and the structure of their emerging social networks. We discovered that failures to mate and successful mating generate distinct emergent group interactions and structures, where sexually deprived males form low density social networks and actively minimize their encounters with other group members, while increasing their aggressive behavior. In addition, sexually deprived male flies elevate the production of seminal fluid proteins (known to facilitate post-mating responses in females) and extend mating duration upon mating with receptive females, altogether leading to reduced re-mating rates. Our results demonstrate the …

We present a detailed description of the experiment realizing for the first time a protective measurement, a novel measurement protocol which combines weak interactions with a “protection mechanism” preserving the measured state coherence during the whole measurement process. Furthermore, protective measurement allows finding the expectation value of an observable, ie, an inherently statistical quantity, by measuring a single particle, without the need for any statistics. This peculiar property, in sharp contrast to the framework of traditional (projective) quantum measurement, might constitute a groundbreaking advance for several quantum technology related fields. View Full-Text

Bohmian mechanics was designed to give rise to predictions identical to those derived by standard quantum mechanics, while invoking a specific interpretation of it - one which allows the classical notion of a particle to be maintained alongside a guiding wave. For this, the Bohmian model makes use of a unique quantum potential which governs the trajectory of the particle. In this work we show that this interpretation of quantum theory naturally leads to the derivation of interesting new phenomena. Specifically, we demonstrate how the fundamental Casimir-Polder force, by which atoms are attracted to a surface, may be temporarily suppressed by utilizing a specially designed quantum potential. We show that when harnessing the quantum potential via a suitable atomic wavepacket engineering, the absorption by the surface can be dramatically reduced. This is proven both analytically and numerically. Finally, an experimental scheme is proposed for achieving the required shape for the atomic wavepacket. All these may enable new insights into Bohmian mechanics as well as new applications to metrology and sensing.

Gas-phase studies of the retinal protonated Schiff base chromophore are reviewed. The use of action spectroscopy has solidified the understanding of the spectral-tuning mechanisms of this important chromophore. Ion-mobility spectrometry and gas phase femtosecond pump-probe spectroscopy studies indicate that several of the remarkable photo-isomerization properties of the chromophore such as its specificity and ultrafast nature are intrinsic properties of the chromophore. With a firm understanding of the properties of the isolated retinal chromophore in terms of spectroscopy and dynamics, the influence of the protein is becoming better understood.

Diamonds contain carbon paramagnetic centers (stable carbon radicals) in small concentrations (at the level of ~1 × 1012 spins/mg) that can help in elucidating the structure of the nitrogen atoms’ contaminants in the diamond crystal. All diamonds that undergo polishing are exposed to high temperatures, owing to the friction force during the polishing process, which may affect the carbon-centered radicals’ concentration and structure. The temperature is increased appreciably; consequently, the black body radiation in the visible range turns orange. During polishing, diamonds emit an orange light (at a wavelength of about 600 nm) that is typical of a black body temperature of 900 °C or higher. Other processes in which color-enhanced diamonds are exposed to high temperatures are thermal treatments or the high-pressure, high-temperature (HPHT) process in which the brown color (resulting from plastic deformation) is bleached. The aim of the study was to examine how thermal treatment and polishing influence the paramagnetic centers in the diamond. For this purpose, four rough diamonds were studied: two underwent a polishing process, and the other two were thermally treated at 650 °C and 1000 °C. The diamonds were analyzed pre- and post-treatment by EPR (Electron Paramagnetic resonance), FTIR (Fourier transform infrared, fluorescence, and their visual appearance. The results indicate that the polishing process results in much more than just thermal heating the paramagnetic centers.

The original version of this article unfortunately contained mistakes. The author name Maria del Mar Dierssen Sotos should read as Mara Dierssen and the author’s affiliations should appear as follows:

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.