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Abstract Promiscuous enzymes often serve as the starting point for the evolution of novel functions. Yet, the extent to which the promiscuity of an individual enzyme can be harnessed several times independently for different purposes during evolution is poorly reported. Here, we present a case study illustrating how NAD(P)+-dependent succinate semialdehyde dehydrogenase of Escherichia coli (Sad) is independently recruited through various evolutionary mechanisms for distinct metabolic demands, in particular vitamin biosynthesis and central carbon metabolism. Using adaptive laboratory evolution (ALE), we show that Sad can substitute for the roles of erythrose 4-phosphate dehydrogenase in pyridoxal 5’-phosphate (PLP) biosynthesis and glyceraldehyde 3-phosphate dehydrogenase in glycolysis. To recruit Sad for PLP biosynthesis and glycolysis, ALE employs various mechanisms, including active site mutation, copy number amplification, and (de)regulation of gene expression. Our study traces down these different evolutionary trajectories, reports on the surprising active site plasticity of Sad, identifies regulatory links in amino acid metabolism, and highlights the potential of an ordinary enzyme as innovation reservoir for evolution.

Abstract Neural systems have evolved not only to solve environmental challenges through internal representations but also, under social constraints, to communicate these to conspecifics. In this work, we aim to understand the structure of these internal representations and how they may be optimized to transmit pertinent information from one individual to another. Thus, we build on previous teacher-student communication protocols to analyze the formation of individual and shared abstractions and their impact on task performance. We use reinforcement learning in grid-world mazes where a teacher network passes a message to a student to improve task performance. This framework allows us to relate environmental variables with individual and shared representations. We compress high-dimensional task information within a low-dimensional representational space to mimic natural language features. In coherence with previous results, we find that providing teacher information to the student leads to a higher task completion rate and an ability to generalize tasks it has not seen before. Further, optimizing message content to maximize student reward improves information encoding, suggesting that an accurate representation in the space of messages requires bi-directional input. These results highlight the role of language as a common representation among agents and its implications on generalization capabilities.

Abstract Anaerobic microbial fermentations provide high product yields and are a cornerstone of industrial bio-based processes. However, the need for redox balancing limits the array of fermentable substrate-product combinations. To overcome this limitation, here we design an aerobic fermentative metabolism that allows the introduction of selected respiratory modules. These can use oxygen to re-balance otherwise unbalanced fermentations, hence achieving controlled respiro-fermentative growth. Following this design, we engineer and characterize an obligate fermentative Escherichia coli strain that aerobically ferments glucose to stoichiometric amounts of lactate. We then re-integrate the quinone-dependent glycerol 3-phosphate dehydrogenase and demonstrate glycerol fermentation to lactate while selectively transferring the surplus of electrons to the respiratory chain. To showcase the potential of this fermentation mode, we direct fermentative flux from glycerol towards isobutanol production. In summary, our design permits using oxygen to selectively re-balance fermentations. This concept is an advance freeing highly efficient microbial fermentation from the limitations imposed by traditional redox balancing.

Abstract 2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is a thiamine diphosphate (ThDP)-dependent versatile enzyme originally discovered in the mammalian α-oxidation pathway. HACL/S natively cleaves 2-hydroxyacyl-CoAs and, in its reverse direction, condenses formyl-CoA with aldehydes or ketones. The one-carbon elongation biochemistry based on HACL/S has enabled the use of molecules derived from greenhouse gases as biomanufacturing feedstocks. We investigated several HACL/S family members with high activity in the condensation of formyl-CoA and aldehydes, and distinct chain-length specificities and kinetic parameters. Our analysis revealed the structures of enzymes in complex with acyl-CoA substrates and products, several covalent intermediates, bound ThDP and ADP, as well as the C-terminal active site region. One of these observed states corresponds to the intermediary α–carbanion with hydroxymethyl-CoA covalently attached to ThDP. This research distinguishes HACL/S from related sub-families and identifies key residues involved in substrate binding and catalysis. These findings expand our knowledge of acyloin-condensation biochemistry and offer attractive prospects for biocatalysis using carbon elongation.

Abstract Coherent interconversion between microwave and optical frequencies can serve as both classical and quantum interfaces for computing, communication, and sensing. Here, we present a compact microwave-optical transducer based on monolithic integration of piezoelectric actuators on silicon nitride photonic circuits. Such an actuator couples microwave signals to a high-overtone bulk acoustic resonator defined by the silica cladding of the optical waveguide core, suspended to enhance electromechanical and optomechanical couplings. At room temperature, this triply resonant piezo-optomechanical transducer achieves an off-chip photon number conversion efficiency of 1.6 × 10−5 over a bandwidth of 25 MHz at an input pump power of 21 dBm. The approach is scalable in manufacturing and does not rely on superconducting resonators. As the transduction process is bidirectional, we further demonstrate the synthesis of microwave pulses from a purely optical input. Capable of leveraging multiple acoustic modes for transduction, this platform offers prospects for frequency-multiplexed qubit interconnects and microwave photonics at large.

Abstract Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy.

Background: E-mental health applications have been increasingly used in the psychotherapeutic care of patients for several years. State-of-the-art sensor technology could be used to determine digital biomarkers for the diagnosis of mental disorders. Furthermore, by integrating sensors into treatment, relevant contextual information (e.g. field of gaze, stress levels) could be made transparent and improve the treatment of people with mental disorders. An overview of studies on this approach would be useful to provide information about the current status quo. Methods: A systematic review of the use of sensor technology in psychotherapy for children and adolescents was conducted with the aim of investigating the use and effectiveness of sensory technology in psychotherapy treatment. Five databases were searched for studies ranging from 2000 to 2023. The study was registered by PROSPERO (CRD42023374219), conducted according to Cochrane recommendations and used the PRISMA reporting guideline. Results: Of the 38.560 hits in the search, only 10 publications met the inclusion criteria, including 3 RCTs and 7 pilot studies with a total of 257 subjects. The study population consisted of children and adolescents aged 6 to 19 years with mental disorders such as OCD, anxiety disorders, PTSD, anorexia nervosa and autistic behavior. The psychotherapy methods investigated were mostly cognitive behavioral therapy (face-to-face contact) with the treatment method of exposure for various disorders. In most cases, ECG, EDA, eye-tracking and movement sensors were used to measure vital parameters. The heterogeneous studies illustrate a variety of potential useful applications of sensor technology in psychotherapy for adolescents. In some studies, the sensors are implemented in a feasible approach to treatment. Conclusion: Sensors might enrich psychotherapy in different application contexts.However, so far there is still a lack of further randomized controlled clinical studies that provide reliable findings on the effectiveness of sensory therapy in psychotherapy for children and adolescents. This could stimulate the embedding of such technologies into psychotherapeutic process.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023374219, identifier [CRD42023374219].

Abstract Superconducting qubits are among the most advanced candidates for achieving fault-tolerant quantum computing. Despite recent significant advancements in the qubit lifetimes, the origin of the loss mechanism for state-of-the-art qubits is still subject to investigation. Furthermore, the successful implementation of quantum error correction requires negligible correlated errors between qubits. Here, we realize long-lived superconducting transmon qubits that exhibit fluctuating lifetimes, averaging 0.2 ms and exceeding 0.4 ms – corresponding to quality factors above 5 million and 10 million, respectively. We then investigate their dominant error mechanism. By introducing novel time-resolved error measurements that are synchronized with the operation of the pulse tube cooler in a dilution refrigerator, we find that mechanical vibrations from the pulse tube induce nonequilibrium dynamics in highly coherent qubits, leading to their correlated bit-flip errors. Our findings not only deepen our understanding of the qubit error mechanisms but also provide valuable insights into potential error-mitigation strategies for achieving fault tolerance by decoupling superconducting qubits from their mechanical environments.

Abstract Background Ultrasound (US) is often the first method used to look for brain or cerebrospinal fluid (CSF) space pathologies. Knowledge of normal CSF width values is essential. Most of the available US normative values were established over 20 years ago, were obtained with older equipment, and cover only part of the age spectrum that can be examined by cranial US. This prospective study aimed to determine the normative values of the widths of the subarachnoid and internal CSF spaces (craniocortical, minimal and maximal interhemispheric, interventricular, and frontal horn) for high-resolution linear US probes in neurologically healthy infants and children aged 0–19 months and assess whether subdural fluid collections can be delineated. Methods Two radiologists measured the width of the CSF spaces with a conventional linear probe and an ultralight hockey-stick probe in neurologically healthy children not referred for cranial or spinal US. Results This study included 359 neurologically healthy children (nboys = 178, 49.6%; ngirls = 181, 50.4%) with a median age of 46.0 days and a range of 1–599 days. We constructed prediction plots, including the 5th, 50th, and 95th percentiles, and an interactive spreadsheet to calculate normative values for individual patients. The measurements of the two probes and the left and right sides did not differ, eliminating the need for separate normative values. No subdural fluid collection was detected. Conclusion Normative values for the widths of the subarachnoid space and the internal CSF spaces are useful for evaluating intracranial pathology, especially when determining whether an increase in the subarachnoid space width is abnormal.

Abstract Chip-scale integration is a key enabler for the deployment of photonic technologies. Coherent laser ranging or FMCW LiDAR, a perception technology that benefits from instantaneous velocity and distance detection, eye-safe operation, long-range, and immunity to interference. However, wafer-scale integration of these systems has been challenged by stringent requirements on laser coherence, frequency agility, and the necessity for optical amplifiers. Here, we demonstrate a photonic-electronic LiDAR source composed of a micro-electronic-based high-voltage arbitrary waveform generator, a hybrid photonic circuit-based tunable Vernier laser with piezoelectric actuators, and an erbium-doped waveguide amplifier. Importantly, all systems are realized in a wafer-scale manufacturing-compatible process comprising III-V semiconductors, silicon nitride photonic integrated circuits, and 130-nm SiGe bipolar complementary metal-oxide-semiconductor (CMOS) technology. We conducted ranging experiments at a 10-meter distance with a precision level of 10 cm and a 50 kHz acquisition rate. The laser source is turnkey and linearization-free, and it can be seamlessly integrated with existing focal plane and optical phased array LiDAR approaches.

IntroductionThe present study investigates the feasibility and usability of a sensor-based eHealth treatment in psychotherapy for pediatric obsessive-compulsive disorder (OCD), and explores the promises and pitfalls of this novel approach. With eHealth interventions, therapy can be delivered in a patient's home environment, leading to a more ecologically valid symptom assessment and access to experts even in rural areas. Furthermore, sensors can help indicate a patient's emotional and physical state during treatment. Finally, using sensors during exposure with response prevention (E/RP) can help individualize therapy and prevent avoidance behavior.MethodsIn this study, we developed and subsequently evaluated a multimodal sensor-based eHealth intervention during 14 video sessions of cognitive-behavioral therapy (CBT) in 20 patients with OCD aged 12-18. During E/RP, we recorded eye movements and gaze direction via eye trackers, and an ECG chest strap captured heart rate (HR) to identify stress responses. Additionally, motion sensors detected approach and avoidance behavior.ResultsThe results indicate a promising application of sensor-supported therapy for pediatric OCD, such that the technology was well-accepted by the participants, and the therapeutic relationship was successfully established in the context of internet-based treatment. Patients, their parents, and the therapists all showed high levels of satisfaction with this form of therapy and rated the wearable approach in the home environment as helpful, with fewer OCD symptoms perceived at the end of the treatment.DiscussionThe goal of this study was to gain a better understanding of the psychological and physiological processes that occur in pediatric patients during exposure-based online treatment. In addition, 10 key considerations in preparing and conducting sensor-supported CBT for children and adolescents with OCD are explored at the end of the article. This approach has the potential to overcome limitations in eHealth interventions by allowing the real-time transmission of objective data to therapists, once challenges regarding technical support and hardware and software usability are addressed. Clinical Trial Registrationwww.ClinicalTrials.gov, identifier (NCT05291611).

ABSTRACT The hydroxyacid glycolate is a highly abundant carbon source in the environment. Glycolate is produced by unicellular photosynthetic organisms and excreted at petagram scales to the environment, where it serves as growth substrate for heterotrophic bacteria. In microbial metabolism, glycolate is first oxidized to glyoxylate by the enzyme glycolate oxidase. The recently described β-hydroxyaspartate cycle (BHAC) subsequently mediates the carbon-neutral assimilation of glyoxylate into central metabolism in ubiquitous Alpha- and Gammaproteobacteria. Although the reaction sequence of the BHAC was elucidated in Paracoccus denitrificans, little is known about the regulation of glycolate and glyoxylate assimilation in this relevant alphaproteobacterial model organism. Here, we show that regulation of glycolate metabolism in P. denitrificans is surprisingly complex, involving two regulators, the IclR-type transcription factor BhcR that acts as an activator for the BHAC gene cluster, and the GntR-type transcriptional regulator GlcR, a previously unidentified repressor that controls the production of glycolate oxidase. Furthermore, an additional layer of regulation is exerted at the global level, which involves the transcriptional regulator CceR that controls the switch between glycolysis and gluconeogenesis in P. denitrificans. Together, these regulators control glycolate metabolism in P. denitrificans, allowing the organism to assimilate glycolate together with other carbon substrates in a simultaneous fashion, rather than sequentially. Our results show that the metabolic network of Alphaproteobacteria shows a high degree of flexibility to react to the availability of multiple substrates in the environment.IMPORTANCEAlgae perform ca. 50% of the photosynthetic carbon dioxide fixation on our planet. In the process, they release the two-carbon molecule glycolate. Due to the abundance of algae, massive amounts of glycolate are released. Therefore, this molecule is available as a source of carbon for bacteria in the environment. Here, we describe the regulation of glycolate metabolism in the model organism Paracoccus denitrificans. This bacterium uses the recently characterized β-hydroxyaspartate cycle to assimilate glycolate in a carbon- and energy-efficient manner. We found that glycolate assimilation is dynamically controlled by three different transcriptional regulators: GlcR, BhcR, and CceR. This allows P. denitrificans to assimilate glycolate together with other carbon substrates in a simultaneous fashion. Overall, this flexible and multi-layered regulation of glycolate metabolism in P. denitrificans represents a resource-efficient strategy to make optimal use of this globally abundant molecule under fluctuating environmental conditions.

Abstract Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH), including PAH associated with connective tissue disease (CTD), and further insights into the management of selexipag‐treated PAH‐CTD patients in clinical settings are needed. These analyses of the ongoing, multicenter, prospective EXPOSURE (EUPAS19085) study describe characteristics, treatment patterns, tolerability, and outcomes of PAH‐CTD patients initiating selexipag in Europe/Canada. All analyses were descriptive, with idiopathic PAH patients who typically display better prognosis included for context. Six hundred ninety‐eight selexipag‐treated patients had follow‐up information; 178 (26%) had PAH‐CTD. The median age was 68 years, patients were predominantly female (88%), and with WHO functional class III symptoms (63%); the median time since diagnosis was 1.7 years. There were 5% patients at low, 25% intermediate‐low, 40% intermediate‐high, and 30% high risk of 1‐year mortality, according to the ESC/ERS 4‐strata risk score. Most (80%) initiated selexipag as a triple oral therapy, and most of these (62%) remained on triple therapy 6 months post‐baseline. Over a median (Q1−Q3) selexipag exposure period of 8.6 (2.5−17.2) months, 79 (44%) patients discontinued selexipag; 36 (20%) due to tolerability/adverse events. Sixty (34%) patients were hospitalized at least once; 120 hospitalizations occurred, with 49 (48%) deemed PAH‐related. Survival at 1 year was 85%, and at 2 years was 71%; 29 (16%) patients died. These results describe the use of combination therapy with selexipag for patients with PAH‐CTD. These findings suggest an opportunity to optimize the benefits of selexipag among patients with PAH‐CTD by moving from escalating after years in response to clinical deterioration to escalating sooner to prevent clinical deterioration.

Abstract The PEGASUS study is the first multicentric and prospective assessment of the safety of air travel flying in pulmonary hypertension (PH) (NCT03051763). Data of air travel from 60 patients with PH was available. No severe adverse events occurred. Nine patients self‐reported mild adverse events during flight (13%), while after landing, 12 patients reported events (20%). Solely one patient (2%) had an adverse event leading to medical consultation. In patients with PH and World Health Organization functional classes II and III, air travel was safe.

The electroencephalogram (EEG) offers a non-invasive means by which a listener's auditory system may be monitored during continuous speech perception. Reliable auditory-EEG decoders could facilitate the objective diagnosis of hearing disorders, or find applications in cognitively-steered hearing aids. Previously, we developed decoders for the ICASSP Auditory EEG Signal Processing Grand Challenge (SPGC). These decoders placed first in the match-mismatch task: given a short temporal segment of EEG recordings, and two candidate speech segments, the task is to identify which of the two speech segments is temporally aligned, or matched, with the EEG segment. The decoders made use of cortical responses to the speech envelope, as well as speech-related frequency-following responses, to relate the EEG recordings to the speech stimuli. Here we comprehensively document the methods by which the decoders were developed. We extend our previous analysis by exploring the association between speaker characteristics (pitch and sex) and classification accuracy, and provide a full statistical analysis of the final performance of the decoders as evaluated on a heldout portion of the dataset. Finally, the generalisation capabilities of the decoders are characterised, by evaluating them using an entirely different dataset which contains EEG recorded under a variety of speech-listening conditions. The results show that the match-mismatch decoders achieve accurate and robust classification accuracies, and they can even serve as auditory attention decoders without additional training.

With the emergence of cyber-physical systems (CPSs) in utility systems like electricity, water, and gas networks, data collection has become more prevalent. While data collection in these systems has numerous advantages, it also raises concerns about privacy as it can potentially reveal sensitive information about users. To address this issue, we propose a Bayesian approach to control the adversarial inference and mitigate the physical-layer privacy problem in CPSs. Specifically, we develop a control strategy for the worst-case scenario where an adversary has perfect knowledge of the user’s control strategy. For finite state-space problems, we derive the fixed-point Bellman’s equation for an optimal stationary strategy and discuss a few practical approaches to solve it using optimization-based control design. Addressing the computational complexity, we propose a reinforcement learning approach based on the Actor-Critic architecture. To also support smart meter privacy research, we present a publicly accessible “Co-LivEn” dataset with comprehensive electrical measurements of appliances in a co-living household. Using this dataset, we benchmark the proposed reinforcement learning approach. The results demonstrate its effectiveness in reducing privacy leakage. Our work provides valuable insights and practical solutions for managing adversarial inference in cyber-physical systems, with a particular focus on enhancing privacy in smart meter applications.