bluuebunny/crossref_metadata_2025 huggingface dataset:
Propensity for Fatigue Failure of the FCBGA UF-Substrate Interface After Prolonged Storage
Authors: Lall Pradeep , Choudhury Padmanava
Published: November 2023

Electronics in automotive applications may be exposed the thermal excursions owing to environmental temperature changes and power-on/off cycling. Temperatures may range from −40C to +200C depending on the location of electronics in the automotive underhood. Flip-chip Ball-Grid Arrays (FCBGAs) are finding applications for advanced driver assistance systems on the automotive platform. Failure of the chip-underfill interface or the substrate-underfill interface is often the precursor for the failure of the flip-chip solder joints. Depending on the power output of the FCBGA package — the top of the chip may have a thermal-interface material to form a low thermal-resistance connection to the lid of the package. Interface reliability under monotonic and repetitive loads after long durations of storage are thus needed for the assessment of the thermo-mechanical reliability of the FCBGA architecture in the automotive underhood environments. In this study UF-Substrate interface reliability has been investigated as a function of Paris’ Constants developed from the samples subjected to 4-point bend fatigue loading. The samples were tested till catastrophic failures, and the critical stress intensity factor (ΔK) was correlated with cycles to failure (da/dN). The slope and the intercept parameters were studied as a function of 4 months’ aging time and 2 temperatures (100°C and 150°C). The evolution of these constants shows the effect of sustained high-temperature operation on the fatigue reliability of 4 underfill interfaces. Several cycles to failure were measured to rank the underfills for future applications in field-deployed electronics.
Optimization of a Air-Cooled Heatsink for Immersion Cooling Application
Authors: Gupta Gautam , Nair Vivek , Pundla Sai Abhideep , Bansode Pratik , Suthar Rohit , Herring Joseph , Lamotte-Dawaghreh Jacob , Sivaraju Krishna Bhavana , Agonafer Dereje , Mynampati Poornima , Sweeney Mike
Published: November 2023

Data centers have started to adopt immersion cooling for more than just mainframes and supercomputers. Due to the inability of air cooling to cool down recent high-configured servers with higher Thermal Design Power, current thermal requirements in machine learning, AI, blockchain, 5G, edge computing, and high-frequency trading have resulted in a larger deployment of immersion cooling. Dielectric fluids are far more efficient at transferring heat than air. Immersion cooling promises to help address many of the challenges that come with air cooling systems, especially as computing densities increase. Immersion-cooled data centers are more expandable, quicker installation, more energy-efficient, allows for the cooling of almost all server components, save more money for enterprises, and are more robust overall. By eliminating active cooling components such as fans, immersion cooling enables a significantly higher density of computing capabilities. When utilizing immersion cooling for server hardware that is intended to be air-cooled, immersion-specific optimized heat sinks should be used. A heat sink is an important component for server cooling efficacy. This research conducts an optimization of heatsink for immersion-cooled servers to achieve the minimum case temperature possible utilizing multi-objective and multidesign variable optimization with pumping power as the constraint.

A high-density server of 3.76 kW was modeled on Ansys Icepak that consists of 2 CPUs and 8 GPUs with heatsink assemblies at their Thermal Design Power along with 32 Dual In-line Memory Modules. The optimization is conducted for Aluminum heat sinks by minimizing the pressure drop and thermal resistance as the objective functions whereas fin count, fin thickness, and heat sink height are chosen as the design variables in all CPUs, and GPUs heatsink assemblies. Optimization for the CPU and the GPU heatsink was done separately and then the optimized heatsinks were tested in an actual test setup of the server in ANSYS Icepak. The dielectric fluid for this numerical study is EC-110 and the cooling is carried out using forced convection. A Design of Experiment (DOE) is created based on the input range of design variables using a full-factorial approach to generate multiple design points. The effect of the design variables is analyzed on the objective functions to establish the parameters that have a greater impact on the performance of the optimized heatsink. The optimization study is done using Ansys OptiSLang where AMOP (Adaptive Metamodel of Optimal Prognosis) as the sampling method for design exploration. The results show total effect values of heat sinks geometric parameters to choose the best design point with the help of a Response Surface 2D and 3D plot for the individual heat sink assembly.
Polarization Curves, Package-Level Multiphysics Simulation of Cu85Al15 and Cu94Al6 WB Corrosion for Automotive and Rugged Environment Applications
Authors: Lall Pradeep , Jung Sungmo
Published: November 2023

Copper wire bonding has increasingly being preferred in place of the more expensive gold wire for chip-to-substrate or chip-to-leadframe interconnects. The copper wire has a higher propensity for corrosion, higher hardness, narrow process window, thinner intermetallics and a higher propensity for cratering owing to a highe splash. Electronics in automotive underhood applications may be routinely expected to function reliability for 10-years, 100K miles. There is lack of foundational data for the assessment of Cu-Al wirebond reliability under humidity and contaminants including Bromine and Chlorine. Exposure to high temperature has been shown to appearance of two new intermetallics Cu85Al15 and Cu94Al6 never studied before for their propensity for corrosion. In this paper, the Cu85Al15 and Cu94Al6 intermetallics have been methodically fabricated using an arc-melter. Polarization curves of the intermetallics have been measured versus operating temperature, annealing duration at 250C, and changes in the pH. For each use-case, the effect of open circuit corrosion current density, open circuit corrosion potential, anodic and cathodic slopes have been quantified. Corrosion rate has been computed for both the intermetallics. The experimental data has been used to formulate a Multiphysics model for the prediction of propensity for corrosion using the Butler-Volmer and Nernst Planck Equations.
Energy Analysis of Rear Door Heat Exchangers in Data Centers With Spatial Workload Distribution
Authors: Simon Vibin Shalom , Karajgikar Saket , Mulay Veerendra , Pundla Sai Abhideep , Sivaraju Krishna Bhavana , Gupta Gautam , Bansode Pratik , Agonafer Dereje
Published: November 2023

Data centers have complex environments that undergo constant changes due to fluctuations in IT load, commissioning and decommissioning of IT equipment, heterogeneous rack architectures and varying environmental conditions. These dynamic factors often pose challenges in effectively provisioning cooling systems, resulting in higher energy consumption. To address this issue, it is crucial to consider data center thermal heterogeneity when allocating workloads and controlling cooling, as it can impact operational efficiency. Computational Fluid Dynamics (CFD) models are used to simulate data center heterogeneity and analyze the impact of two different cooling mechanisms on operational efficiency. This research focuses on comparing the cooling based on facility water for Rear Door Heat Exchanger (RDHx) and conventional Computer Room Air Conditioning (CRAH) systems in two different data center configurations. Efficiency is measured in terms of ΔT across facility water. Higher ΔT will result in efficient operation of chillers. The actual chiller efficiency is not calculated as it would depend on local ambient conditions in which the chiller is operated.

The first data center model represents a typical enterpriselevel configuration where all servers and racks have homogeneous IT power. The second model represents a colocation facility where server/rack power configurations are randomly distributed. These models predict temperature variations at different locations based on IT workload and cooling parameters. Traditionally, CRAH configurations are selected based on total IT power consumption, rack power density, and required cooling capacity for the entire data center space. On the other hand, RDHx can be scaled based on individual rack power density, offering localized cooling advantages. Multiple workload distribution scenarios were simulated for both CRAH and RDHx-based data center models. The results showed that RDHx provides a uniform thermal profile across the data center, irrespective of server/rack power density or workload distribution. This characteristic reduces the risk of over- or under-provisioning racks when using RDHx. Operational efficiency is compared in terms of difference in supply and return temperature of facility water for CRAH and RDHx units based on spatial heat dissipation and workload distribution. RDHx demonstrated excellent cooling capabilities while maintaining a higher ΔT, resulting in reduced cooling energy consumption, operational carbon footprint (?), and water usage.
Numerical Study of a Piezoelectric Vibration Energy Harvester Without and With an Ortho-Planar Spring Using a Modified H-Shape Structure
Authors: Taufan Ibnu , Punch Jeff , Nico Valeria
Published: November 2023

The demand for low-power electronic devices in wireless sensor networks (WSNs) has been continuously increasing. Most WSNs rely on battery power, however, and batteries need replacement regularly, resulting in direct and indirect pollution to the environment. Because of its abundance in many environments, kinetic energy, in the form of ambient vibrations, could be used as alternative to batteries by using vibrational energy harvesting techniques. Piezoelectric materials are one of the most common form of transducers and, traditionally, piezoelectric vibrational energy harvesters (PVEHs) are based on a cantilever beam, with one or more piezoelectric layers. However, the drawbacks of such designs are single vibration mode and narrow frequency bandwidth.

In this paper, we propose a novel PVEH design based on a modified H-shape structure without and with an ortho-planar spring to solve the issues of single vibration mode and narrow frequency bandwidth. This structure comprises a double clamped beam, with four arms which act like cantilever beams. The centre of the structure is coupled with a compliant ortho-planar spring to create low natural frequency and multiple peaks in the frequency response. A proof mass is placed on the spring to induce high stresses in the structure.

A numerical model using finite element analysis (FEA) was developed using the solid mechanics, electrostatics, and electrical circuit modules in COMSOL Multiphysics to compare the output voltage and power of the modified H-shape structure without (baseline) and with an ortho-planar spring (design 1) in the x, y, z axes. The H-shape structure was made of polylactide (PLA) as a substrate. The configuration used six PZT-5H piezoelectric materials connected in parallel, a 17.78 kΩ load resistor, and 0.4 g (g = 9.81 m/s2) base excitation.

The results show that: (i) the first three modes of design 1 are 8.9, 15.6, and 17.2 Hz, while the baseline design’s modes are 11.8, 15.3, and 17.6 Hz; (ii) both of designs show a multi-modal response, and that design 1 has three peaks, while the baseline has two peaks in the frequency range (0–50 Hz) in the z axis; (iii) both designs can only harvest energy efficiently in the z axis; and (iv) the baseline design achieves maximum voltage and power values of 34.5 V and 33.5 mW respectively, whereas design 1 produces 31.3 V and 27.6 mW respectively in the z axis.
Aero-Structural Response of a Slitted Bistable Laminate
Authors: Boddapati Karthik , Boston D. Matthew , Rivas-Padilla Jose R. , Arrieta Andres F.
Published: November 2023

Compliant morphing structures have been explored in aircraft as potential alternatives to rigid hinge-based mechanisms because of their ability to undergo large deformations without complicated assemblies. The simple geometry, high strength-to-weight ratio, and selective stiffness of bistable composite laminates make them highly suitable for use in morphing structures. However, rectangular asymmetric laminates with one edge clamped lose their bistability at low aspect ratios (free edge length to clamped edge length). Introducing multiple slits parallel to the free edge of these laminates has previously been shown to enable natural curving, thereby preserving their bistability. In this work, we characterize the behavior of a slitted bistable laminate under aerodynamic loading. The laminate is mounted to a bluff body leading edge inside a wind tunnel. The lift and drag forces acting on the two stable states of the slitted laminate are measured at two different flow speeds of 10 m/s and 20 m/s, and angles of attack ranging from −10 degrees to +10 degrees. We compare these results to those of a conventional bistable laminate with the same geometry to understand how the addition of slits affects the associated aerodynamics.
In Situ Actuation of Shape Memory Alloy Using Focused Ultrasound
Authors: Chipana Aldo , Hill Jeffrey R. , Dillon Christopher R.
Published: November 2023

Nitinol (NiTi) shape memory alloy exhibits excellent characteristics for use in biomedical engineering. The material has excellent biocompatibility, corrosion resistance, and wear characteristics, which has increased its use in biomedical applications, including stents and guidewires. While NiTi is becoming more common in medical procedures, most of the use has relied on the superelasticity of the wire, rather than its hysteretic qualities. One reason for this is the difficulty in heating NiTi wire in situ, without damaging adjacent tissue. This research explores the use of focused ultrasound to noninvasively heat NiTi wire above its transition temperature. To demonstrate the memory effect, the wire is strained at low temperature, then placed between porcine muscle samples to mimic an in situ biological environment. Using focused ultrasound, the wire is heated until the NiTi actuates and its shape memory is recovered. Embedded thermocouples located close to the wire measure the local temperature. The study found that higher ultrasonic power resulted in (1) faster actuation of the Nitinol, (2) more complete Nitinol actuation, and (3) lower temperatures in the surrounding tissue with less thermal damage.
Experimental Study on Gradually Varying Thickness Patch for Elastic Wave Manipulation Using Piezo Disk Actuators
Authors: Park Hyun-Su , Hwang Dae-Hyun , Han Jae-Hung
Published: November 2023

In recent years, there have been several studies focused on manipulating elastic waves in thin plate structures to achieve shock reduction or energy harvesting, without being limited by frequency. An elastic patch is a promising method for such manipulation, as it can be easily applied to practical structures without compromising their stiffness or strength. Refraction of the bending wave is achieved by mismatching the effective stiffness between the host plate and the region where the patch is attached. In this study, we explored the characteristics of GVT (Gradually Varying Thickness) patches for elastic wave manipulation, modeling various types of patches (such as triangular wedge/pyramid and circular cone) and predicting wave paths using ray-tracing and density estimation algorithms. For experimental investigation, an out-of-plane vibration scanning system with a 2D auto-stage and an LDV (Laser Doppler Vibrometer) was built, and a 1-D array of 15 piezoelectric-disk actuators was attached to the host plate for generating bending waves. All the patches showed excellent performance for shock reduction in specific areas, and their propagation paths were compared with ray-tracing results. The proposed method has potential applications in protecting sensitive components from intensive shock or noise without any degradation of structural stiffness or strength.
Fabrication and Characterization of Flexible Matrix Composite Wafers
Authors: Hada Masaki , Philen Michael
Published: November 2023

Flexible Matrix Composites (FMCs) are high performance actuators that exhibit a high mechanical advantage when pressurized. These actuators rely on symmetric layers of carbon fiber surrounding a flexible rubber tube. When the fiber angle is less than 55 degrees with respect to the longitudinal axis, these actuators expand radially and contract in length when pressurized. When these actuators are coiled in a disk-shaped wafer, the radial volume change within the composite actuator can be utilized to create a compressive force through the thickness. By varying the actuation pressure, matrix material, fiber winding angle, and inner tubing diameter, the actuation and stiffness properties can be widely varied and suited to the desired application. This research aims to determine the impact on wafer performance by the variation of design parameters. It has been found that increasing the matrix material modulus will increase the overall stiffness of the wafer, while also increasing the maximum load that can be applied. Inversely, a lower modulus matrix will decrease the overall stiffness of the wafer, with the benefit of greater actuation volume. For each combination of fiber and matrix selection, there exists a stratum of pressures allowing for active stiffness and force management during use. From this comprehensive evaluation, a characterization of the wafer performance through experimentation will be reported.
Embedded Sensing and Localization of Pressure in Silicone Skin Using Sensors Printed From CNF/TPU Filament
Authors: Meier Joseph L. , Turnbull Steven A. , Hernandez Julio A. , Maynard Cole , Rodriguez David , Newell Brittany , Tallman Tyler N.
Published: November 2023

Additive manufacturing (AM) provides a near-infinite design space to create unique and custom components. Recent advances have enabled the development of novel self-sensing materials for fused filament fabrication (FFF) AM, which have potential applications in areas such as soft robotics, smart textiles, embedded structural sensing, and, among others, biomedicine. Sensing in these fields is often done using traditional strain sensors that have limited capability for large deformations and little-to-no customizability. Through the use of piezoresistive filaments, AM has the potential to create highly customizable, application-specific sensors. However, the widespread adoption of self-sensing filament has been constrained due to developmental challenges, such as low conductivity and inconsistent or highly variable electrical properties. To address these issues, in this work, we manufacture a modified thermoplastic polyurethane (TPU) filament with 10 wt.% carbon nanofiber (CNF) inclusions using a novel wet-mixing technique previously developed within our research group. This CNF/TPU filament is flexible and has consistent electrical properties. Building on the extensive use of self-sensing composites in soft robotic applications, the CNF/TPU filament was embedded into a soft silicone skin to demonstrate sensing and localization of pressure points applied to the skin via simple electrical measurements taken from the printed and embedded CNF/TPU sensors. These preliminary results highlight the incredible potential and far-reaching design space of AM-produced sensors.
An Integrated Audio-Tactile Interface Based on Dielectric Elastomer Actuators for User Interaction
Authors: Gratz-Kelly Sebastian , Holz Benedikt , Krüger Tim , Seelecke Stefan , Rizzello Gianluca , Motzki Paul , Moretti Giacomo
Published: November 2023

Due to their high actuation energy density, high stretchability and self-sensing capability, dielectric elastomer actuators (DEAs) and sensors are very attractive for the field of user interaction and communication. The possibility of using the same element to perform actuation (feedback) and sensing (user input detection), in particular, opens up possibilities towards highly integrated interaction elements.

Here, we present an integrated prototype of a DEA user interface that can produce different feedbacks (acoustic, vibrotactile) in response to a user’s touch. Touch detection is achieved by means of capacitive sensing, whereas multi-sensory actuation (tactile and acoustic feedbacks) is produced leveraging on the dynamic modal response of the DEA membrane, whose different vibration modes are used to produce linear actuation (used to convey vibrotactile stimulations) at low frequencies, and structural vibrations (for generating sound) at higher frequencies. The prototype includes an acoustic enclosure, compact sensing/control electronics, and a custom-built low-cost compact high voltage (HV) power amplifier.

We characterize the coupled system response (DEA + custom amplifier) in terms of linear actuation (in the range 0–180 Hz) and sound pressure output (in the range 500–2500 Hz) and compare results with those obtained with a commercially available HV bench power supply. The performance of the proposed system is comparable to that obtained with commercial electronics in terms of linear displacements and sound pressure level, while it introduces higher harmonic distortions in specific ranges of the acoustic response.

The concept and results presented here represent a step forward towards further integration and down-scaling of DEA user interfaces.
Hybrid Soft-Rigid Joint With Inherent Sensing and Actuation Capabilities Based on Rolled Dielectric Elastomers
Authors: Meyer Andreas , Schmidt Christian Johannes , Motzki Paul
Published: November 2023

Traditionally the tension structures are built by passive wires unable to give information about the state of the system or to excite an actuation from within. Using dielectric elastomers (DEs) to distribute tension forces, both can be achieved within the structure itself. DEs are thin silicone membranes that are printed with a flexible, conductive electrode on both sides, resulting in a capacitor with variable geometry. To integrate slim DEs that can not only be used as actuators and sensors but also assume the role of passive tension elements, the membrane is being rolled up to be used as a stiffer, centrical elastomer beam which is called a rolled dielectric elastomer (RDE). These smart elements are characterized by capacitance-displacement and force-displacement measurements. Especially the linearity of the sensor signal in relation to the applied stretch allows for a good displacement reconstruction, while this work concentrates on the first design and feasibility investigation. Here a first table like tensegrity structure has been designed based on RDEs as soft displacement elements. The structure has been built and tested with an integrated sensing electronic for simultaneous sensor monitoring.
Estimation of Stress State in an Axially Loaded Beam Using Modal Data
Authors: Gosavi Hrishikesh , Malladi Vijaya V. N. Sriram
Published: November 2023

Residual stresses are found to play a vital role in the dynamic behavior of the beam. These stresses are sometimes induced unintentionally due to manufacturing processes where temperate plays a role, while at other times, beams are subjected to stresses to alter their dynamic behavior for a particular application. Owing to the ubiquitous presence of the stressed beam, the estimation of its stress state becomes imperative to prevent structural failures. This study employs an approach to estimate the stress state of a beam from the natural frequencies and mode shapes. Using the modal data, the wave-numbers are calculated, and hence a dispersion relation is established. Modal analysis for a beam subjected to axial load is performed in a standard finite element software package, and the natural frequencies and the mode shapes are extracted. The analysis is performed for different values of loads, both compressive and tensile. The dispersion relation for the load cases is calculated, and the relationship between the wave-number, natural frequency, and load value is established using a curve-fitting approach. It was found that the discussed approach estimated the load value accurately. The discussed approach can be utilized to estimate the buckling of structures and stress states in a beam directly from the experimental data of the axially loaded beam.
A balancing act: investigations on the impact of altered signal sensitivity in bacterial quorum sensing
Authors: Miranda Samantha Wellington , Greenberg E. Peter
Published: November 2023

Many bacterial species communicate and cooperate with kin using a form of cell-cell signaling called quorum sensing. Sensitivity and selectivity are fundamental properties of quorum sensing, and of cell signaling more generally, as they dictate the ability of cells to accurately detect and interpret signals. In this study, we investigate the impact of signal sensitivity on gene regulation and on bacterial fitness using two variants of the LasR quorum sensing receptor in the opportunistic pathogen
Pseudomonas aeruginosa
. Our studies reinforce that altering LasR signal-binding residues tends to result in decreased signal selectivity. We also find that LasR hyper-sensitivity results in earlier and stronger expression of LasR-regulated genes, whereas hypo-sensitivity results in delayed transcription from both LasR- and RhlR-regulated promoters. Furthermore, strains expressing either the hyper- or hypo-sensitive LasR polypeptide exhibit reduced production of pyocyanin, a key antimicrobial that impacts intra- and interspecies competition as well as pathogenicity. These changes to gene expression underscore the complex regulatory network by which
P. aeruginosa
controls group behaviors. Ultimately, altered signal sensitivity results in a fitness defect for LasR hyper-sensitive cells during kin competition against wild-type
P. aeruginosa
and for hypo-sensitive cells during interspecies competition against the opportunistic pathogen
Burkholderia multivorans
. Our findings highlight the delicate balance between group behaviors regulated by quorum sensing and bacterial fitness and contribute to a better understanding of the evolutionary pressures that may tune sensitivity in cell-cell signaling.

IMPORTANCE

Quorum sensing (QS) is a widespread form of cell-cell signaling that regulates group behaviors important for competition and cooperation within bacterial communities. The QS systems from different bacterial species have diverse properties, but the functional consequences of this diversity are largely unknown. Taking advantage of hyper- and hypo-sensitive QS receptor variants in the opportunistic pathogen
Pseudomonas aeruginosa
, we examine the costs and benefits of altered signal sensitivity. We find that the sensitivity of a model QS receptor, LasR, impacts the timing and level of quorum gene expression, and fitness during intra- and interspecies competition. These findings suggest competition with kin and with other bacterial species work together to tune signal sensitivity.
Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance
Authors: Pei Luxin , Overdahl Kirsten E. , Shannon John P. , Hornick Katherine M. , Jarmusch Alan K. , Hickman Heather D.
Published: November 2023

Vaccinia virus (VACV) infection induces prominent changes in host cell metabolism. Little is known about the global metabolic reprogramming that takes place in whole tissue during viral infection. Here, we performed a longitudinal metabolomics study in VACV-infected mouse skin to investigate metabolic changes in the tissue during infection. We assessed metabolites in homogenized skin of the ear pinnae over time in the presence or absence of antigen-specific T cells using untargeted mass spectrometry. VACV infection induced several significant metabolic changes in the tissue, including in the levels of nucleic acid metabolites (reflecting the impact of viral replication on the skin metabolome). Furthermore, monocyte- and antiviral T cell-produced metabolites, such as itaconic acid and glutamine, were significantly increased following infection, highlighting the immune response’s contribution to the global skin metabolome. Additional RNA-Seq of infected skin tissue recapitulated metabolic changes identified by metabolomics analysis. Overall, our study reveals the metabolic balance of viral replication and the antiviral immune response in the skin, elucidating metabolic pathways that could contribute to cutaneous poxvirus control
in vivo
.

IMPORTANCE

Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur
in vivo
during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.
Genome sequences of Mx1, the first
Myxococcus
phage isolated, and Mx4, a generalized transducing myxophage
Authors: López-Rojo Alfonso , Jackson Simon A. , Bernal-Bernal Diego , Galbis-Martínez Marisa , Fineran Peter C. , Elías-Arnanz Montserrat
Published: November 2023

Myxococcus xanthus
is the best-studied member of the phylum Myxococcota, but the bacteriophages infecting it and their characterization remain limited. Here, we present complete genomes of Mx1, the first
Myxococcus
phage isolated, and of an Mx4 derivative widely used for generalized transduction, both unclassified Caudoviricetes with long, contractile tails.
Identification of an anti-CRISPR protein that inhibits the CRISPR-Cas type I-B system in
Clostridioides difficile
Authors: Muzyukina Polina , Shkaruta Anton , Guzman Noemi M. , Andreani Jessica , Borges Adair L. , Bondy-Denomy Joseph , Maikova Anna , Semenova Ekaterina , Severinov Konstantin , Soutourina Olga
Published: November 2023

CRISPR-Cas systems provide prokaryotic hosts with adaptive immunity against mobile genetic elements. Many bacteriophages encode anti-CRISPR (Acr) proteins that inhibit host defense. The identification of Acr proteins is challenging due to their small size and high sequence diversity, and only a limited number has been characterized to date. In this study, we report the discovery of a novel Acr protein, AcrIB2, encoded by the φCD38-2
Clostridioides difficile
phage that efficiently inhibits interference by the type I-B CRISPR-Cas system of the host and likely acts as a DNA mimic. Most
C. difficile
strains contain two
cas
operons, one encoding a full set of interference and adaptation proteins and another encoding interference proteins only. Unexpectedly, we demonstrate that only the partial operon is required for interference and is subject to inhibition by AcrIB2.

IMPORTANCE

Clostridioides difficile
is the widespread anaerobic spore-forming bacterium that is a major cause of potentially lethal nosocomial infections associated with antibiotic therapy worldwide. Due to the increase in severe forms associated with a strong inflammatory response and higher recurrence rates, a current imperative is to develop synergistic and alternative treatments for
C. difficile
infections. In particular, phage therapy is regarded as a potential substitute for existing antimicrobial treatments. However, it faces challenges because
C. difficile
has highly active CRISPR-Cas immunity, which may be a specific adaptation to phage-rich and highly crowded gut environment. To overcome this defense,
C. difficile
phages must employ anti-CRISPR mechanisms. Here, we present the first anti-CRISPR protein that inhibits the CRISPR-Cas defense system in this pathogen. Our work offers insights into the interactions between
C. difficile
and its phages, paving the way for future CRISPR-based applications and development of effective phage therapy strategies combined with the engineering of virulent
C. difficile
infecting phages.
Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity
Authors: Martínez-Arribas Blanca , Annang Frederick , Díaz-González Rosario , Pérez-Moreno Guiomar , Martín Jesús , Mackenzie Thomas A. , Castillo Francisco , Reyes Fernando , Genilloud Olga , Ruiz-Pérez Luis Miguel , Vicente Francisca , Ramos María C. , González-Pacanowska Dolores
Published: November 2023

Human coronaviruses cause respiratory tract infections and are of great importance due to the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Human betacoronavirus OC43 (HCoV-OC43) is an adequate surrogate for SARS-CoV-2 because it infects the human respiratory system, presents a comparable biology, and is transmitted in a similar way. Its use is advantageous since it only requires biosafety level 2 infrastructure that minimizes costs and biosafety-associated limitations. In this report, we describe a high-throughput screening platform to identify compounds that inhibit the propagation of HCoV-OC43. Optimization of assays, based on inhibition of the cytopathic effect and virus immunodetection with a specific antibody, has provided a robust methodology for the screening of a selection of microbial natural product extracts from the Fundación MEDINA collection. Using this approach, a subset of 1,280 extracts has been explored. Of these, upon hit confirmation and early liquid chromatography mass spectrometry (LC-MS) dereplication, 10 extracts that contain potential new compounds were identified. In addition, we report on the novel antiviral activity of some previously described natural products whose presence in bioactive extracts was confirmed by LC-MS analysis.

IMPORTANCE

The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1,280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity.
Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs
Authors: Bagato Ola , Balkema-Buschmann Anne , Todt Daniel , Weber Saskia , Gömer André , Qu Bingqian , Miskey Csaba , Ivics Zoltan , Mettenleiter Thomas C. , Finke Stefan , Brown Richard J. P. , Breithaupt Angele , Ushakov Dmitry S.
Published: November 2023

Lung immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the ability to deal with infection. Using light sheet fluorescence microscopy of hamster lung slices in combination with virological, immunohistochemical, and RNA sequencing analyses, we show a wave of monocyte-derived macrophage (MDM) infiltration and the antiviral response which follows the spread of SARS-CoV-2 through the lungs and lead to virus elimination. These innate immune processes are related to the onset of necrotizing inflammatory and remodeling responses, which manifest as extensive cell death, vascular damage, and cell proliferation. We show that MDM appear in parallel with virus clearance and endothelial injury. Prothrombotic factor upregulation, tissue repair, and alveolar cell proliferation result in tissue remodeling, which is followed by fibrosis despite a decrease in inflammatory and antiviral activities. Although the lung tissue integrity is repaired, longer-term alterations of the lung arise as an outcome of concurrent tissue damage and regeneration processes.

IMPORTANCE

We present the first study of the 3D kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the early host response in a large lung volume using a combination of tissue imaging and transcriptomics. This approach allowed us to make a number of important findings:

Spatially restricted antiviral response is shown, including the formation of monocytic macrophage clusters and upregulation of the major histocompatibility complex II in infected epithelial cells.

The monocyte-derived macrophages are linked to SARS-CoV-2 clearance, and the appearance of these cells is associated with post-infection endothelial damage; thus, we shed light on the role of these cells in infected tissue.

An early onset of tissue repair occurring simultaneously with inflammatory and necrotizing processes provides the basis for longer-term alterations in the lungs.
Erratum to: Thermodynamic Model of the Fluid System H2O–CO2–NaCl–CaCl2 at P-T Parameters of the Middle and Lower Crust
Authors: Ivanov M. V.
Published: November 2023

An Erratum to this paper has been published: https://doi.org/10.1134/S0869591123340027
Non-typhoidalSalmonella enteritidisprosthetic valve endocarditis
Authors: van Kruijsbergen Bas W A , Spiegelenberg Janneke P , van Lieshout Maarten , Heuvelmans Maarten
Published: November 2023

In this case, we present a rare cause of prosthetic valve endocarditis. A man in his 80s presented to the emergency department with fever and diarrhoea. The patient underwent a transcatheter aortic valve replacement 17 years earlier. A negative PCR result in faeces forSalmonellaand positive blood cultures withSalmonellagave rise to the suspicion of an intravascularSalmonellainfection, which was confirmed with a positron emission tomography. Due to the low prevalence ofSalmonellaendocarditis, there is no consensus on the most effective treatment. Guidelines recommend early surgery and long-term antimicrobial treatment in endocarditis with Gram-negative bacteria. In this case, surgery was not deemed feasible given the patient his advanced age and multiple comorbidities. Despite treatment with intravenous antibiotics, the patient succumbed to progression of endocarditis 37 days after admission.
Combination of computed tomography measurements and flexible video bronchoscope guidance for accurate placement of the right-sided double-lumen tube: a randomised controlled trial
Authors: Li Jian , Qian Yingcong , Lei Yishan , Huo Wenwen , Xu Mingzhu , Zhang Yuanyuan , Ji Qiuyuan , Yang Jianping , Liu Huayue , Hou Yongheng
Published: November 2023

Objective

To compare the modified strategy for the right-sided double-lumen tube (R-DLT) placement using a combination of CT measurements and flexible video bronchoscopy guidance with traditional bronchoscopy technique.

Trial design, setting and participants

Double-blind, parallel randomised control trial at a tertiary care medical centre in China. 100 patients undergoing video-assisted thoracoscopic surgery and requiring R-DLT were randomly allocated to the control group and the intervention group.

Intervention

The control group used the traditional bronchoscopy-guided technique. In the intervention group, the length and anteroposterior diameter of the right main bronchus (RMB) were measured on CT images to select the side and size of the Rüsch tube, and then a black depth marker was placed on the tube according to the difference between the length of the RMB and the bronchial cuff. Under the guidance of bronchoscopy, the depth marker should be placed parallel to the tracheal carina and a characteristic white line on the tube should be parallel to the midline of the tracheal carina.

Main outcomes

The primary endpoint was the positioning of right upper lobe (RUL) ventilatory slot and RUL bronchial orifice. The secondary endpoints included intubation data and perioperative adverse events.

Results

Compared with the control group, our modified strategy significantly increased the optimal and acceptable position rate (76% vs 98%, respectively; p<0.039), decreased the replacement rate (80% vs 94%; p=0.042), shortened the intubation time (101.4±7.3 s vs 75.2±8.1 s; p=0.019) and reduced the incidence of transient hypoxaemia (25% vs 6%; p=0.022), subglottic resistance (20% vs 6%; p=0.037), tracheobronchial injury (35% vs 13%; p=0.037) and postoperative RUL collapse (15% vs 2%; p=0.059).

Conclusion

This study demonstrates the superiority of our strategy and provides a new viable method for R-DLT placement.

Trial registration number

Chinese Clinical Trial Registry (ChiCTR1900021676).
Burden, determinants, consequences and care of multimorbidity in rural and urbanising Telangana, India: protocol for a mixed-methods study within the APCAPS cohort
Authors: Lieber Judith , Banjara Santosh Kumar , Mallinson Poppy Alice Carson , Mahajan Hemant , Bhogadi Santhi , Addanki Srivalli , Birk Nick , Song Wenbo , Shah Anoop SV , Kurmi Om , Iyer Gowri , Kamalakannan Sureshkumar , Kishore Galla Raghu , Sadanand Shilpa , Dasi Teena , Kulkarni Bharati , Kinra Sanjay
Published: November 2023

Introduction

The epidemiological and demographic transitions are leading to a rising burden of multimorbidity (co-occurrence of two or more chronic conditions) worldwide. Evidence on the burden, determinants, consequences and care of multimorbidity in rural and urbanising India is limited, partly due to a lack of longitudinal and objectively measured data on chronic health conditions. We will conduct a mixed-methods study nested in the prospective Andhra Pradesh Children and Parents’ Study (APCAPS) cohort to develop a data resource for understanding the epidemiology of multimorbidity in rural and urbanising India and developing interventions to improve the prevention and care of multimorbidity.

Methods and analysis

We aim to recruit 2100 APCAPS cohort members aged 45+ who have clinical and lifestyle data collected during a previous cohort follow-up (2010–2012). We will screen for locally prevalent non-communicable, infectious and mental health conditions, alongside cognitive impairments, disabilities and frailty, using a combination of self-reported clinical diagnosis, symptom-based questionnaires, physical examinations and biochemical assays. We will conduct in-depth interviews with people with varying multimorbidity clusters, their informal carers and local healthcare providers. Deidentified data will be made available to external researchers.

Ethics and dissemination

The study has received approval from the ethics committees of the National Institute of Nutrition and Indian Institute of Public Health Hyderabad, India and the London School of Hygiene and Tropical Medicine, UK. Meta-data and data collection instruments will be published on the APCAPS website alongside details of existing APCAPS data and the data access process (www.lshtm.ac.uk/research/centres-projects-groups/apcaps).
Longitudinal outcome monitoring in patients with chronic gastroduodenal symptoms investigated using the Gastric Alimetry system: study protocol
Authors: Varghese Chris , Dachs Nicky , Schamberg Gabriel , McCool Kiel , Law Mikaela , Xu William , Calder Stefan , Foong Daphne , Ho Vincent , Daker Charlotte , Andrews Christopher N , Gharibans Armen A , O'Grady Gregory
Published: November 2023

Introduction

The Gastric Alimetry platform offers a multimodal assessment of gastric function through body surface gastric mapping (BSGM) and concurrent symptom-tracking via a validated App. We aim to perform a longitudinal cohort study to examine the impact of Gastric Alimetry, and changes in clinical management on patient symptoms, quality of life and psychological health.

Methods and analysis

This is a prospective multicentre longitudinal observational cohort study of participants with chronic gastroduodenal symptoms. Consecutive participants undergoing Gastric Alimetry will be invited to participate. Quality of life will be assessed via EuroQol-5D and the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score. Gastrointestinal symptoms will be assessed via the Patient Assessment of Upper Gastrointestinal Symptom Severity index, and the Gastroparesis Cardinal Symptom Index. Psychometrics will be assessed, including anxiety via the General Anxiety Disorder-7, perceived stress using the Perceived Stress Scale 4, and depression via the Patient Health Questionnaire 9. Clinical parameters including diagnoses, investigations and treatments (medication and procedures) will also be captured. Assessments will be made the week after the BSGM test, at 30 days, 90 days, 180 days and 360 days thereafter. The primary outcome is feasibility of longitudinal follow-up of a cohort that have undergone Gastric Alimetry testing; from which patients’ continuum of care can be characterised. Secondary outcomes include changes in patient-reported symptoms, quality of life and psychometrics (anxiety, stress and depression). Inferential causal analyses will be performed at the within patient level to explore causal associations between treatment changes and clinical outcomes. The impact of Gastric Alimetry on clinical management will also be captured.

Ethics and dissemination

The protocol has been approved in Aotearoa New Zealand by the Auckland Health Research Ethics Committee. Results will be submitted for conference presentation and peer-reviewed publication.
Chronic kidney disease and functional impairment in a longitudinal study of older adults in China
Authors: Duan Xiaoyu , Wang Lingdian , Wei Wei , Wang Zhifeng , Zhang Xiaoli , Liu Jianjun , Ding Degang
Published: November 2023

Objectives

To examine the associations of chronic kidney disease (CKD) with dynamic functional impairment among older Chinese adults.

Design

This was a prospective longitudinal study.

Setting

Data were derived from the Chinese Longitudinal Healthy Longevity Study.

Participants

All adults aged ≥60 years were potentially eligible. This study included 2970 participants.

Primary outcome measures

CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Functional performances included instrumental activities of daily living (IADL) and basic activities of daily living (BADL), which were measured using six daily activities, including eating, dressing, transferring, using the toilet, bathing and continence, and eight daily activities, including visiting neighbours, shopping, cooking, washing clothes, walking 1 km, lifting 5 kg, crouching and standing up three times and taking public transportation, respectively.

Results

This study included 2970 participants, including 988 (33.60%) participants with CKD. Participants with CKD had higher IADL scores than those without CKD (β=0.895, 95% CI: 0.761 to 1.029). Furthermore, there was a significant linear trend in the association of CKD severity with the IADL score (p<0.001). Similarly, CKD was significantly associated with higher BADL scores (β=0.067, 95% CI: 0.017 to 0.118). However, only participants with moderate and advanced CKD had a higher BADL score (β=0.088 and 0.152, 95% CI: 0.006 to 0.171 and 0.019 to 0.286, respectively).

Conclusions

CKD was associated with worse functional impairment. Furthermore, there was a significant linear trend in the association of the severity of CKD with the IADL score. However, only participants with moderate and advanced CKD had higher BADL scores.