bluuebunny/crossref_metadata_2025 huggingface dataset:
Sparse bounds for the bilinear spherical maximal function
Authors: Borges Tainara , Foster Benjamin , Ou Yumeng , Pipher Jill , Zhou Zirui
Published: January 2023

We derive sparse bounds for the bilinear spherical maximal function in any dimension . When , this immediately recovers the sharp bound of the operator and implies quantitative weighted norm inequalities with respect to bilinear Muckenhoupt weights, which seems to be the first of their kind for the operator. The key innovation is a group of newly developed continuity improving estimates for the single‐scale bilinear spherical averaging operator.
Activation mechanisms and structural dynamics of STIM proteins
Authors: Sallinger Matthias , Grabmayr Herwig , Humer Christina , Bonhenry Daniel , Romanin Christoph , Schindl Rainer , Derler Isabella
Published: January 2023

The family of stromal interaction molecules (STIM) includes two widely expressed single‐pass endoplasmic reticulum (ER) transmembrane proteins and additional splice variants that act as precise ER‐luminal Ca2+ sensors. STIM proteins mainly function as one of the two essential components of the so‐called Ca2+ release‐activated Ca2+ (CRAC) channel. The second CRAC channel component is constituted by pore‐forming Orai proteins in the plasma membrane. STIM and Orai physically interact with each other to enable CRAC channel opening, which is a critical prerequisite for various downstream signalling pathways such as gene transcription or proliferation. Their activation commonly requires the emptying of the intracellular ER Ca2+ store. Using their Ca2+ sensing capabilities, STIM proteins confer this Ca2+ content‐dependent signal to Orai, thereby linking Ca2+ store depletion to CRAC channel opening. Here we review the conformational dynamics occurring along the entire STIM protein upon store depletion, involving the transition from the quiescent, compactly folded structure into an active, extended state, modulation by a variety of accessory components in the cell as well as the impairment of individual steps of the STIM activation cascade associated with disease.

image
Design and Thermal Performance Research of Airfoil Alkali Metal High-Temperature Heat Pipe
Authors: Wang Changji , Li Jinwang , Xu Bowen , Wei Zhiyong
Published: January 2023

An integrated airfoil alkali metal high-temperature heat pipe structure is proposed for the air rudder. The heat transfer properties of lithium and sodium are analyzed, and the equal-thickness test pieces are designed and prepared. The sonic limit, condensation limit, viscosity limit, entrainment limit, capillary limit and boiling limit are calculated theoretically, and the corresponding feasible working areas are drawn according to each limit curve. It is found that the optimal working temperature range of the test piece is 800∼1500 K. The effects of heating power and placement angle on the start-up time, isothermal performance, and heat transfer performance of the test piece are studied by experiments. The increase in heating power is helpful to shorten the start-up time and improve the isothermal performance and heat transfer performance of the test piece. The placement angle has little effect on the start-up time, but it has an effect on the isothermal performance and heat transfer performance.
Impact of Operating Conditions and Axial Casing Grooves on the Evolution of Flow Structure Across Blade Rows in an Axial Compressor
Authors: Saraswat Ayush , Koley Subhra Shankha , Katz Joseph
Published: January 2023

Stereo particle image velocimetry (SPIV) measurements in a series of axial planes investigate the impact of operating conditions and semicircular axial casing grooves (ACGs) on the evolution of flow structure across multiple blade rows in an axial compressor. The field of view extends radially from the hub to the tip and circumferentially over entire blade passages. Previous studies in this machine have shown that the ACGs improve the stall margin significantly but reduce the peak efficiency. At pre-stall flowrate and without ACGs, intermittent reverse axial flow near the casing is induced by backflow vortices, tip leakage vortex (TLV), and the leakage flow extend upstream of the rotor leading edge. Inside the rotor, the tip region blockage, characterized by low axial and high circumferential momentum, expands radially inward as the flow evolves axially. This extreme non-uniformity diminishes rapidly within the stator. In addition to previously shown ACGs effects, the current data reveal that the flow jetting out from the groove upstream of the rotor generates axially aligned vortices on both sides of each jet. These vortices substantially reduce the flow non-uniformity over the entire passage by entraining the faster mid-span flow into the tip region. Near the best efficiency point, the jets become weaker, the blockage is confined to the tip region, and differences between the global flow structure with and without ACGs become subtle. However, interactions of the TLV with secondary flows entrained from the grooves into the passage expand the TLV signature, which has adverse effects on the compressor performance.
Experimental and Computational Investigation of an Advanced Casing Treatment in a Single-Stage High-Speed Compressor
Authors: Maher Nicholas H. , Ross Mark H. , Morris Scott C. , Priebe Stephan , Jothiprasad Giridhar , Allan David , McNulty Gregory , Macrorie Michael , Mallina Ramakrishna
Published: January 2023

An advanced casing treatment (CT) design was tested in a single-stage, high-speed axial compressor. The geometry of the casing included bent-axial slots applied near the rotor leading edge. Compressor performance and stall margin (SM) measurements were acquired for both casing treatment and for the smooth wall case at four different corrected speeds. The measurements also included rotor-exit radial traverses of unsteady total pressure. The results indicated an increase in rotor pressure ratio at all operating conditions with the application of the casing treatment. The stall margin also increased at all rotor speeds. Efficiency increases were observed with the casing treatment at design conditions and some off-design conditions. Numerical simulations of the IGV, rotor, and stator were conducted with and without the casing treatment. These results served to validate the efficacy of the part-wheel unsteady Reynolds-averaged Navier–Stokes (URANS) simulations to predict the effects of the casing treatment. The simulations also allowed a detailed study of the flow physics related to the interactions between the rotor and casing.
Nonlinear Flutter Analysis of Labyrinth Seals
Authors: Corral Roque , Greco Michele , Matabuena Luis
Published: January 2023

A simple nonlinear model to describe labyrinth seal flutter has been developed to assess the aeromechanic stability of straight-through labyrinth seals subjected to large gap variations. The model solves the one-dimensional integral mass, momentum, and energy equations of the seal for a prescribed motion numerically until a periodic state is reached. The model accounts for the effect, previously neglected, of high clearance variations on the stability. The results show that when the vibration amplitudes are small, the work-per-cycle coincides with the prediction of the Corral and Vega model (2018, “Conceptual Flutter Analysis of Labyrinth Seals Using Analytical Models. Part I: Theoretical Background,” ASME J. Turbomach., 140(10), p. 121006) and Corral et al. (2021, “Higher-Order Conceptual Model for Seal Flutter,” ASME J. Turbomach., 143(7), p. 071006), but for large vibration amplitudes nonlinearities alter the stability limit. In realistic cases, when the discharge time of the seal is much longer than the vibration period, the nonlinear effects are significant and tend to increase the unstable range of operating conditions. Furthermore, seals supported either on the high-pressure or low-pressure sides, stable for small vibration amplitudes, can destabilize when the vibration amplitude increases. The linear stability, though close in many situations to the nonlinear threshold, is not conservative, and attention must be paid to nonlinear effects.
Development of a New Manufacturing Route by Direct Laser Metal Deposition With NiCrSiFeB Alloys to Replace Cobalt in Aeronautical Components
Authors: Pereira Juan Carlos , Zubiri Fidel , Aguilar David , Taboada Maria Del Carmen , Guillonneau Gaylord , Rocchi Jerome
Published: January 2023

Nickel-based NiCrSiFeB alloy (Ni-Cr-Si-B self-fluxing family) are excellent candidates for replacing Cobalt-based alloys in aeronautical components such as sealing rings, valve seats, sliding bearing seats, etc. In this type of components, commonly manufactured by centrifugal casting and conventional processes, high temperature wear and stiffness under complex thermo-mechanical stresses cause lack of sealing and an increase in the wear rate. Metal additive manufacturing by direct laser metal deposition with powder (p-LMD) is presented as a potential manufacturing route for the complex processing of this type of alloys. This research work deals with the development of a new manufacturing route using p-LMD that ranges from the proper selection of the chemical composition for the starting powders, the development of the LMD process parameters to tackle the challenges associated to the wide solidification range and crack susceptibility of Ni-Cr-Si-B alloys, its monitoring and control, as well as the post-processing required to achieve the manufacture of aeronautical components. In this work, the porosity analysis, as-built microstructure, hardness at room temperature and at high temperature, and the strengthening mechanisms have been studied in cylinders manufactured with different chemical composition grades and LMD process parameter sets (slow, normal and fast deposition speed).
Effect of Heat Treatment on Structure and Properties of Laser Powder Bed Fusion Inconel 939
Authors: Nandha Kumar E. , Athira K. S. , Chatterjee Subhradeep , Srinivasan Dheepa
Published: January 2023

Additive manufacturing of high gamma prime (γ’) Nickel-based superalloys are challenging due to their hot cracking tendency. This study comprises an understanding of microstructural evolution and mechanical properties of Inconel 939 (IN939) alloy processed via laser powder bed fusion (LPBF). The as-printed samples comprised of columnar grains along the build direction with a pronounced <100> texture resulting in ∼17% lower elastic modulus along the build direction as compared to the builds in transverse orientation. The microstructure consists of cellular and columnar dendrites with segregation of Nb, Ta and Si in the inter-dendritic regions (decorating the cell boundaries). Occurrence of fine (< 50 nm) intra granular carbides in the as printed condition is a unique feature of this microstructure. Heat treatment resulted in dissolution of the dendritic microstructure with precipitation of semi-coherent γ’ (Ni3(Al,Ti)) precipitates (150–200 nm) homogeneously from the matrix resulting in ∼16% enhanced yield strength. The <100> texture is retained even after the solution and aging heat treatment indicating thermal stability of this structure.
Dimensional Deviation Prediction Model Based on Scale and Material Concentration Effects for LPBF Process
Authors: Ben Amor Sabrine , Zongo Floriane , Louhichi Borhen , Tahan Antoine , Brailovski Vladimir
Published: January 2023

Additive Manufacturing (AM) processes generate parts layer-by-layer without using formative tools. The resulting advantages highlight the capability of AM to become an inherent part of product development. However, process-specific challenges such as high surface roughness, the stair-stepping effect, or dimensional deviations inhibit the establishment of AM at the industrial scale. Thus, AM parts often need to be post-processed using established manufacturing processes. Many process parameters and geometrical factors influence the dimensional accuracy in AM. Published results relating to these deviations are also difficult to compare because they are based on several geometries that are manufactured using different processes, materials, and machine settings. Laser Powder Bed Fusion (LPBF) is gaining in popularity, but one of the obstacles facing its larger industrial use is the limited knowledge of its dimensional and geometrical performances. Therefore, using it requires studying the process and improving the accuracy of the parts involved. This paper represents a new attempt to predict dimensional deviations of LPBF parts. During the project, the scale- and material concentration-related phenomena were implemented in a new image analysis model and applied to the as-built part. We carried out a comparison between the results of the proposed model with those obtained from numerical analyses and experiments. The model does not use finite element analysis, takes less time to compute, and provides reasonable prediction accuracy.
From Photopolymerization of Metal Suspension to Practical and Economical Additive Manufacturing of Haynes 214 Alloy for High Temperature Application
Authors: Nguyen Hoa Xuan , Suen Hawke , Poudel Bibek , Qu Zhiyuan , Ahmad Mohsan Uddin , Kwon Patrick , Benard Andre , Chung Haseung
Published: January 2023

Haynes 214 high temperature heat exchanger assembly with enclosed heat flow channels and internal fin structures was successfully fabricated using our scalable and expeditious additive manufacturing (SEAM) process, a new metal additive manufacturing (AM) technology developed at Michigan State University (MSU). Three dimensional green objects can be fabricated by selectively photopolymerizing Haynes 214 metal suspension on a powder bed system in a layer-by-layer fashion. An innovative strategy to attain a complete binder removal and high density as well as dimensional accuracy were developed and employed to achieve final metal parts with relative density above 99.5% and no geometrical distortion.
Performance on stochastic figure-ground perception varies with individual differences in speech-in-noise recognition and working memory capacity
Authors: Johns Michael A. , Calloway Regina C. , Phillips Ian , Karuzis Valerie P. , Dutta Kelsey , Smith Ed , Shamma Shihab A. , Goupell Matthew J. , Kuchinsky Stefanie E.
Published: January 2023

Speech recognition in noisy environments can be challenging and requires listeners to accurately segregate a target speaker from irrelevant background noise. Stochastic figure-ground (SFG) tasks in which temporally coherent inharmonic pure-tones must be identified from a background have been used to probe the non-linguistic auditory stream segregation processes important for speech-in-noise processing. However, little is known about the relationship between performance on SFG tasks and speech-in-noise tasks nor the individual differences that may modulate such relationships. In this study, 37 younger normal-hearing adults performed an SFG task with target figure chords consisting of four, six, eight, or ten temporally coherent tones amongst a background of randomly varying tones. Stimuli were designed to be spectrally and temporally flat. An increased number of temporally coherent tones resulted in higher accuracy and faster reaction times (RTs). For ten target tones, faster RTs were associated with better scores on the Quick Speech-in-Noise task. Individual differences in working memory capacity and self-reported musicianship further modulated these relationships. Overall, results demonstrate that the SFG task could serve as an assessment of auditory stream segregation accuracy and RT that is sensitive to individual differences in cognitive and auditory abilities, even among younger normal-hearing adults.
Development and validation of a Spanish-language spatial release from masking task in a Mexican population
Authors: Lelo de Larrea-Mancera E. Sebastian , Solís-Vivanco Rodolfo , Sánchez-Jimenez Yolanda , Coco Laura , Gallun Frederick J. , Seitz Aaron R.
Published: January 2023

This study validates a new Spanish-language version of the Coordinate Response Measure (CRM) corpus using a well-established measure of spatial release from masking (SRM). Participants were 96 Spanish-speaking young adults without hearing complaints in Mexico City. To present the Spanish-language SRM test, we created new recordings of the CRM with Spanish-language Translations and updated the freely available app (PART; https://ucrbraingamecenter.github.io/PART_Utilities/) to present materials in Spanish. In addition to SRM, we collected baseline data on a battery of non-speech auditory assessments, including detection of frequency modulations, temporal gaps, and modulated broadband noise in the temporal, spectral, and spectrotemporal domains. Data demonstrate that the newly developed speech and non-speech tasks show similar reliability to an earlier report in English-speaking populations. This study demonstrates an approach by which auditory assessment for clinical and basic research can be extended to Spanish-speaking populations for whom testing platforms are not currently available.
Effects of nonlinear internal gravity waves on normal-incident reflection measurements of seafloor sediments
Authors: Chen Tzu-Ting , Chiu Linus Y.-S. , Lin Ying-Tsong
Published: January 2023

Sonar data acquired by sub-bottom profilers and echosounder systems are widely used to estimate geoacoustic properties of marine sediments. However, the uncertainty of the seabed property estimates caused by water-column variability may limit the application. In this paper, the acoustic focusing and defocusing effects of nonlinear internal gravity waves on normal-incident acoustic reflection measurements are studied. The experiment data were collected in the South China Sea from two transceiver moorings located at two different sites, one of which contained strong nonlinear internal waves (NIWs), while another site did not. The observed reflection intensity variation at the internal wave site varied up to 10 dB. On the other hand, the bottom reflections at the other site without internal waves were stable, and a seafloor sediment sample collected there was analyzed to validate the sediment type inferred from bottom loss. Numerical simulations using ray-tracing and parabolic equation models confirmed the cause of this intensity fluctuation by the acoustic focusing and defocusing of NIWs. This study eventually showed that NIWs may induce a significant bias for geoacoustic property estimates from seabed reflection coefficients.
A Minimal Sensor Inertial Measurement Unit System Is Replicable and Capable of Estimating Bilateral Lower-Limb Kinematics in a Stationary Bodyweight Squat and a Countermovement Jump
Authors: Fain AuraLea , Hindle Benjamin , Andersen Jordan , Nindl Bradley C. , Bird Matthew B. , Fuller Joel T. , Wills Jodie A. , Doyle Tim L.A.
Published: January 2023

This study aimed to validate a 7-sensor inertial measurement unit system against optical motion capture to estimate bilateral lower-limb kinematics. Hip, knee, and ankle sagittal plane peak angles and range of motion (ROM) were compared during bodyweight squats and countermovement jumps in 18 participants. In the bodyweight squats, left peak hip flexion (intraclass correlation coefficient [ICC] = .51), knee extension (ICC = .68) and ankle plantar flexion (ICC = .55), and hip (ICC = .63) and knee (ICC = .52) ROM had moderate agreement, and right knee ROM had good agreement (ICC = .77). Relatively higher agreement was observed in the countermovement jumps compared to the bodyweight squats, moderate to good agreement in right peak knee flexion (ICC = .73), and right (ICC = .75) and left (ICC = .83) knee ROM. Moderate agreement was observed for right ankle plantar flexion (ICC = .63) and ROM (ICC = .51). Moderate agreement (ICC > .50) was observed in all variables in the left limb except hip extension, knee flexion, and dorsiflexion. In general, there was poor agreement for peak flexion angles, and at least moderate agreement for joint ROM. Future work will aim to optimize methodologies to increase usability and confidence in data interpretation by minimizing variance in system-based differences and may also benefit from expanding planes of movement.
Design of a pan-betacoronavirus vaccine candidate through a phylogenetically informed approach
Authors: Lewitus Eric , Bai Hongjun , Rolland Morgane
Published: January 2023

Coronaviruses are a diverse family of viruses that crossed over into humans at least seven times, precipitating mild to catastrophic outcomes. The severe acute respiratory syndrome coronavirus 2 pandemic renewed efforts to identify strains with zoonotic potential and to develop pan-coronavirus vaccines. The analysis of 2181 coronavirus genomes (from 102 host species) confirmed the limited sequence conservation across genera (alpha-, beta-, delta-, and gammacoronavirus) and proteins. A phylogenetically informed pan-coronavirus vaccine was not feasible because of high genetic heterogeneity across genera. We focused on betacoronaviruses and identified nonhuman-infecting receptor binding domain (RBD) sequences that were more genetically similar to human coronaviruses than expected given their phylogenetic divergence. These human-like RBDs defined three phylogenetic clusters. A vaccine candidate based on a representative sequence for each cluster covers the diversity estimated to protect against existing and future human-infecting betacoronaviruses. Our findings emphasize the potential value of conceptualizing prophylaxis against zoonoses in terms of genetic, rather than species, diversity.
Tree mycorrhizal association types control biodiversity-productivity relationship in a subtropical forest
Authors: Deng Meifeng , Hu Shuijin , Guo Lulu , Jiang Lin , Huang Yuanyuan , Schmid Bernhard , Liu Chao , Chang Pengfei , Li Shan , Liu Xiaojuan , Ma Keping , Liu Lingli
Published: January 2023

Mycorrhizae are symbiotic associations between terrestrial plants and fungi in which fungi obtain nutrients in exchange for plant photosynthates. However, it remains unclear how different types of mycorrhizae affect their host interactions and productivity. Using a long-term experiment with a diversity gradient of arbuscular (AM) and ectomycorrhizal (EcM) tree species, we show that the type of mycorrhizae critically controls the effect of diversity on productivity. With increasing diversity, the net primary production of AM trees increased, but EcM trees decreased, largely because AM trees are more effective in acquiring nitrogen and phosphorus. Specifically, with diversity increase, AM trees enhance both nutrient resorption and litter decomposition, while there was a trade-off between litter decomposability and nutrient resorption in EcM trees. These results provide a mechanistic understanding of why AM trees using a different nutrient acquisition strategy from EcM trees can dominate in subtropical forests and at the same time their diversity enhances productivity.
Leaping liquid crystal elastomers
Authors: Hebner Tayler S. , Korner Kevin , Bowman Christopher N. , Bhattacharya Kaushik , White Timothy J.
Published: January 2023

Snap-through mechanisms are pervasive in everyday life in biological systems, engineered devices, and consumer products. Snap-through transitions can be realized in responsive materials via stimuli-induced mechanical instability. Here, we demonstrate a rapid and powerful snap-through response in liquid crystalline elastomers (LCEs). While LCEs have been extensively examined as material actuators, their deformation rate is limited by the second-order character of their phase transition. In this work, we locally pattern the director orientation of LCEs and fabricate mechanical elements with through-thickness (functionally graded) modulus gradients to realize stimuli-induced responses as fast as 6 ms. The rapid acceleration and associated force output of the LCE elements cause the elements to leap to heights over 200 times the material thickness. The experimental examination in functionally graded LCE elements is complemented with computational evaluation of the underlying mechanics. The experimentally validated model is then exercised as a design tool to guide functional implementation, visualized as directional leaping.
The structure of DarB in complex with Rel
NTD
reveals nonribosomal activation of Rel stringent factors
Authors: Ainelo Andres , Caballero-Montes Julien , Bulvas Ondřej , Ernits Karin , Coppieters ‘t Wallant Kyo , Takada Hiraku , Craig Sophie Z. , Mazzucchelli Gabriel , Zedek Safia , Pichová Iva , Atkinson Gemma C. , Talavera Ariel , Martens Chloe , Hauryliuk Vasili , Garcia-Pino Abel
Published: January 2023

Rel stringent factors are bifunctional ribosome-associated enzymes that catalyze both synthesis and hydrolysis of the alarmones (p)ppGpp. Besides the allosteric control by starved ribosomes and (p)ppGpp, Rel is regulated by various protein factors depending on specific stress conditions, including the c-di-AMP–binding protein DarB. However, how these effector proteins control Rel remains unknown. We have determined the crystal structure of the DarB
2
:Rel
NTD
2
complex, uncovering that DarB directly engages the SYNTH domain of Rel to stimulate (p)ppGpp synthesis. This association with DarB promotes a SYNTH-primed conformation of the N-terminal domain region, markedly increasing the affinity of Rel for ATP while switching off the hydrolase activity of the enzyme. Binding to c-di-AMP rigidifies DarB, imposing an entropic penalty that precludes DarB-mediated control of Rel during normal growth. Our experiments provide the basis for understanding a previously unknown mechanism of allosteric regulation of Rel stringent factors independent of amino acid starvation.
A carnivorous mushroom paralyzes and kills nematodes via a volatile ketone
Authors: Lee Ching-Han , Lee Yi-Yun , Chang Yu-Chu , Pon Wen-Li , Lee Sue-Ping , Wali Niaz , Nakazawa Takehito , Honda Yoichi , Shie Jiun-Jie , Hsueh Yen-Ping
Published: January 2023

The carnivorous mushroom
Pleurotus ostreatus
uses an unknown toxin to rapidly paralyze and kill nematode prey upon contact. We report that small lollipop-shaped structures (toxocysts) on fungal hyphae are nematicidal and that a volatile ketone, 3-octanone, is detected in these fragile toxocysts. Treatment of
Caenorhabditis elegans
with 3-octanone recapitulates the rapid paralysis, calcium influx, and neuronal cell death arising from fungal contact. Moreover, 3-octanone disrupts cell membrane integrity, resulting in extracellular calcium influx into cytosol and mitochondria, propagating cell death throughout the entire organism. Last, we demonstrate that structurally related compounds are also biotoxic to
C. elegans
, with the length of the ketone carbon chain being crucial. Our work reveals that the oyster mushroom has evolved a specialized structure containing a volatile ketone to disrupt the cell membrane integrity of its prey, leading to rapid cell and organismal death in nematodes.
Remote control of muscle-driven miniature robots with battery-free wireless optoelectronics
Authors: Kim Yongdeok , Yang Yiyuan , Zhang Xiaotian , Li Zhengwei , Vázquez-Guardado Abraham , Park Insu , Wang Jiaojiao , Efimov Andrew I. , Dou Zhi , Wang Yue , Park Junehu , Luan Haiwen , Ni Xinchen , Kim Yun Seong , Baek Janice , Park Joshua Jaehyung , Xie Zhaoqian , Zhao Hangbo , Gazzola Mattia , Rogers John A. , Bashir Rashid
Published: January 2023

Bioengineering approaches that combine living cellular components with three-dimensional scaffolds to generate motion can be used to develop a new generation of miniature robots. Integrating on-board electronics and remote control in these biological machines will enable various applications across engineering, biology, and medicine. Here, we present hybrid bioelectronic robots equipped with battery-free and microinorganic light-emitting diodes for wireless control and real-time communication. Centimeter-scale walking robots were computationally designed and optimized to host on-board optoelectronics with independent stimulation of multiple optogenetic skeletal muscles, achieving remote command of walking, turning, plowing, and transport functions both at individual and collective levels. This work paves the way toward a class of biohybrid machines able to combine biological actuation and sensing with on-board computing.
Allergy: Mechanistic insights into new methods of prevention and therapy
Authors: Akdis Cezmi A. , Akdis Mübeccel , Boyd Scott D. , Sampath Vanitha , Galli Stephen J. , Nadeau Kari C.
Published: January 2023

In the past few decades, the prevalence of allergic diseases has increased worldwide. Here, we review the etiology and pathophysiology of allergic diseases, including the role of the epithelial barrier, the immune system, climate change, and pollutants. Our current understanding of the roles of early life and infancy; diverse diet; skin, respiratory, and gut barriers; and microbiome in building immune tolerance to common environmental allergens has led to changes in prevention guidelines. Recent developments on the mechanisms involved in allergic diseases have been translated to effective treatments, particularly in the past 5 years, with additional treatments now in advanced clinical trials.
Multiplex epigenome editing of
MECP2
to rescue Rett syndrome neurons
Authors: Qian Junming , Guan Xiaonan , Xie Bing , Xu Chuanyun , Niu Jacqueline , Tang Xin , Li Charles H. , Colecraft Henry M. , Jaenisch Rudolf , Liu X. Shawn
Published: January 2023

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of methyl CpG-binding protein 2 (
MECP2
) on the X chromosome in young females. Reactivation of the silent wild-type
MECP2
allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the
MECP2
promoter by dCas9-Tet1 with target single-guide RNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation-edited
MECP2
locus by dCpf1-CTCF (a catalytically dead Cpf1 fused with CCCTC-binding factor) with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases.
Frequent Transmission of Streptococcus pneumoniae Serotype 35B and 35D, Clonal Complex 558 Lineage, across Continents and the Formation of Multiple Clades in Japan
Authors: Shinohara Koh , Fujisawa Takao , Chang Bin , Ito Yutaka , Suga Shigeru , Matsumura Yasufumi , Yamamoto Masaki , Nagao Miki , Ohnishi Makoto , Sugai Motoyuki , Nakano Satoshi
Published: January 2023

Streptococcus pneumoniae
is a common bacterial pathogen that causes infections in children worldwide, even after administration of the pneumococcal conjugate vaccine.
S. pneumoniae
serotype 35B, especially the clonal complex 558 (CC558) lineage, has emerged globally following implementation of the 13-valent pneumococcal conjugate vaccine. Serotype 35B strains are also associated with multidrug resistance to both β-lactams and non-β-lactam drugs.
Elongation Factor P Is Important for Sporulation Initiation
Authors: Feaga Heather A. , Hong Hye-Rim , Prince Cassidy R. , Rankin Ananda , Buskirk Allen R. , Dworkin Jonathan
Published: January 2023

Elongation factor P (EF-P) is a universally conserved translation factor that prevents ribosome stalling at amino acids that form peptide bonds with low efficiency, particularly polyproline tracts. Phenotypes associated with EF-P deletion are pleiotropic, and the mechanistic basis underlying many of these phenotypes is unclear.
Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease
Authors: Vallabh Sonia M. , Zou Dan , Pitstick Rose , O’Moore Jill , Peters Janet , Silvius Derek , Kriz Jasna , Jackson Walker S. , Carlson George A. , Minikel Eric Vallabh , Cabin Deborah E.
Published: January 2023

There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program.
A Heterologous Challenge Rescues the Attenuated Immunogenicity of SARS-CoV-2 Omicron BA.1 Variant in Syrian Hamster Model
Authors: Ma Jian , Liu Xuan , Zhou Ming , Chen Peiwen , Chen Rirong , Wang Jia , Zhu Huachen , Wu Kun , Ye Jianghui , Zhang Yali , Yuan Quan , Tang Qiyi , Yuan Lunzhi , Cheng Tong , Guan Yi , Xia Ningshao
Published: January 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant causes breakthrough infections among convalescent patients and vaccinated populations. However, Omicron does not generate robust cross-protective responses.
Analysis of Pneumocystis Transcription Factor Evolution and Implications for Biology and Lifestyle
Authors: Ames Ryan , Brown Alistair J. P. , Gudelj Ivana , Nev Olga A.
Published: January 2023

Pneumocystis jirovecii
is a major fungal pathogen of humans that infects healthy individuals, colonizing the lungs of infants. In immunocompromised and transplant patients, this fungus causes life-threatening pneumonia, and these
Pneumocystis
infections remain among the most common and serious infections in HIV/AIDS patients.
Nanopore-Targeted Sequencing Improves the Diagnosis and Treatment of Patients with Serious Infections
Authors: Zhang Yi , Lu Xuan , Tang Liang V. , Xia Linghui , Hu Yu
Published: January 2023

We introduce the application of NTS in blood samples of patients with serious infections and expound the efficiency and accuracy of NTS in detecting pathogenic microorganisms. Our work builds on the considerable interest of the scientific community in the management of serious infection.
Microbiome Features Differentiating Unsupervised-Stratification-Based Clusters of Patients with Abnormal Glycometabolism
Authors: Xu Ting , Wang Xuejiao , Chen Yu , Li Hui , Zhao Liping , Ding Xiaoying , Zhang Chenhong
Published: January 2023

The gut microbiota is altered in patients with type 2 diabetes (T2D) and prediabetes. The association of particular bacteria with T2D, however, varied among studies, which has made it challenging to develop precision medicine approaches for the prevention and alleviation of T2D.
Inhibition of Ribosome Assembly and Ribosome Translation Has Distinctly Different Effects on Abundance and Paralogue Composition of Ribosomal Protein mRNAs in Saccharomyces cerevisiae
Authors: Shamsuzzaman Md , Rahman Nusrat , Gregory Brian , Bommakanti Ananth , Zengel Janice M. , Bruno Vincent M. , Lindahl Lasse
Published: January 2023

Mutations in genes for ribosomal proteins or assembly factors cause a variety of diseases called ribosomopathies. These diseases are typically ascribed to a reduction in the cell’s capacity for protein synthesis.
Identification of a Rho-Dependent Termination Site
In Vivo
Using Synthetic Small RNA
Authors: Wang Xun , N Monford Paul Abishek , Jeon Heung Jin , He Jin , Lim Heon M.
Published: January 2023

sysRNA, which was formerly widely employed, has steadily lost popularity as more novel techniques for suppressing gene expression come into existence because of issues such as unstable inhibition effect and low inhibition efficiency. However, it remains an interesting topic as a regulatory tool due to its ease of design and low metabolic burden on cells.
An XDR Pseudomonas aeruginosa ST463 Strain with an IncP-2 Plasmid Containing a Novel Transposon Tn
6485f
Encoding
bla
IMP-45
and
bla
AFM-1
and a Second Plasmid with Two Copies of
bla
KPC-2
Authors: Fang Yinfei , Wang Nanfei , Wu Zhaoxia , Zhu Yijun , Ma Yongjun , Li Yue , Cai Heng , Zhang Piaopiao , Leptihn Sebastian , Yu Yunsong , Hua Xiaoting , Tu Yuexing
Published: January 2023

The ST463 clone is an emerging high-risk sequence type that is spreading with
bla
KPC-2
-containing plasmids. The core
bla
KPC-2
genetic platform is IS
Kpn27
-b
la
KPC-2
-IS
Kpn6
in almost all samples, and the adjacent region beyond the core platform varies by IS
26
-mediated inversion or duplication events, amplifying the
bla
KPC-2
gene copies.
Barnase-barstar Specific Interaction Regulates Car-T Cells Cytotoxic Activity toward Malignancy
Authors: Kalinin R. S. , Shipunova V. O. , Rubtsov Y. P. , Ukrainskay V. M. , Schulga A. , Konovalova E. V. , Volkov D. V. , Yaroshevich I. A. , Moysenovich A. M. , Belogurov A. A. , Telegin G. B. , Chernov A. S. , Maschan M. A. , Terekhov S. S. , Knorre V. D. , Khurs E. , Gnuchev N. V. , Gabibov A. G. , Deyev S. M.
Published: January 2023

The development of CAR-T specific therapy made a revolution in modern oncology. Despite the pronounced therapeutic effects, this novel approach displayed several crucial limitations caused by the complications in pharmacokinetics and pharmacodynamics controls. The presence of the several severe medical complications of CAR-T therapy initiated a set of attempts aimed to regulate their activity in vivo. We propose to apply the barnase-barstar system to control the cytotoxic antitumor activity of CAR-T cells. To menage the regulation targeting effect of the system we propose to use barstar-modified CAR-T cells together with barnase-based molecules. Barnase was fused with designed ankyrin repeat proteins (DARPins) specific to tumor antigens HER2 (human epidermal growth factor receptor 2) The application of the system demonstrates the pronounced regulatory effects of CAR-T targeting.
Response to bipolar androgen therapy and PD-1 inhibition in a patient with metastatic castration-resistant prostate cancer and a germlineCHEK2mutation
Authors: Berger Benjamin T , Labriola Matthew K , Antonarakis Emmanuel S , Armstrong Andrew J
Published: January 2023

We present the case of a patient with germlineCHEK2-mutated metastatic castration-resistant prostate cancer (mCRPC) who responded to bipolar androgen therapy (BAT) combined with pembrolizumab after progressing through multiple lines of therapy. The patient was diagnosed in his 40s following an elevated screening prostate-specific antigen and biopsy. Over the course of 20 years, he progressed through nearly all standard therapies including androgen deprivation, combined androgen blockade, traditional chemotherapy, targeted therapies and experimental agents. He was ultimately treated with BAT, whereby the patient’s cycle was between low (castrate) and high (supraphysiological) testosterone levels. This counterintuitive approach resulted in a marked response to BAT plus pembrolizumab consolidation lasting 13 months. His underlying germline mutation inCHEK2, an important mediator of DNA repair, may have sensitised the cancer cells to the DNA damage caused by BAT. Single case report outcomes should not be used as evidence of efficacy for treatment regimes. Our case supports further investigation into BAT plus immunotherapy for patients with DNA repair-deficient mCRPC.
Chondrosarcoma of the thyroid cartilage: surgical management of a rare case
Authors: Kinsella Anna , Corbett Mel , Hacking Sean , Lang John
Published: January 2023

Laryngeal malignancy encompasses about 1% of all cancers. Chondrosarcoma in the head and neck region represents about 0.1% of head and neck malignancies. Typical presenting symptoms relate to the anatomical location of these tumours and include dysphonia, inspiratory stridor, dysphagia, odynophagia or a neck mass. Benign and malignant cartilaginous cancers of the larynx have been described, and preoperative diagnosis can be difficult. Our report highlights the surgical management of a male patient in his 50s with chondrosarcoma of the thyroid cartilage.
Differentiating stages of functional vision loss from glaucoma using the Disc Damage Likelihood Scale and cup:disc ratio
Authors: Philippin Heiko , Matayan Einoti Naino , Knoll Karin Marianne , Macha Edith , Mbishi Sia , Makupa Andrew , Matsinhe Cristóvão Daniel , da Gama Isac Vasco , Monjane Mário Jorge , Ncheda Joyce Awum , Mulobuana Francisco Alcides Francisco , Muna Elisante , Guylene Nelly Fopoussi , Gazzard Gus , Marques Ana Patricia , Shah Peter , Macleod David , Makupa William , Burton Matthew J
Published: January 2023

Background

Glaucoma staging is critical for treatment planning but has rarely been tested in severe/end-stage disease. We compared the performance of the Disc Damage Likelihood Scale (DDLS) and cup:disc ratio (CDR) using a functional glaucoma staging system (GSS) as the reference standard.

Methods

Post hoc analysis of a randomised controlled trial at the Eye Department of Kilimanjaro Christian Medical Centre, Tanzania. Eligible participants (aged ≥18 years) with open-angle glaucoma, intraocular pressure (IOP) of >21 mm Hg, were randomised to timolol 0.5% eye drops or selective laser trabeculoplasty. Fundoscopy established vertical and horizontal CDRs and DDLS. Visual acuity and static visual fields were graded (GSS). The study used area under the receiver operating characteristic (AROC) curves and Spearman’s rank correlation coefficients to compare staging systems. Logistic regression with generalised estimating equations determined risk factors of functional severe/end-stage glaucoma.

Results

382 eyes (201 participants) were evaluated; 195 (51%) had severe or end-stage glaucoma; mean IOP was 26.7 (SD 6.9) mm Hg. DDLS yielded an AROC of 0.90 (95% CI 0.87 to 0.93), vertical cup:disc ratio (vCDR) of 0.88 (95% CI 0.85 to 0.91, p=0.048) for identifying severe/end-stage disease. Correlation coefficients comparing GSS to DDLS and vCDRs were 0.73 and 0.71, respectively. Advanced structural stages, vision impairment, higher IOP and less financial resources were risk factors of functional severe/end-stage glaucoma.

Conclusion

This study indicates that both structural staging systems can differentiate severe/end-stage glaucoma from less severe disease, with a moderate advantage of DDLS over CDR. Clinical examination of the optic disc plays an important role in addition to functional assessment when managing severe/end-stage glaucoma.
London International Consensus and Delphi study on hamstring injuries part 1: classification
Authors: Paton Bruce M , Court Nick , Giakoumis Michael , Head Paul , Kayani Babar , Kelly Sam , Kerkhoffs Gino M M J , Moore James , Moriarty Peter , Murphy Simon , Plastow Ricci , Pollock Noel , Read Paul , Stirling Ben , Tulloch Laura , van Dyk Nicol , Wilson Mathew G , Wood David , Haddad Fares
Published: January 2023

Muscle injury classification systems for hamstring injuries have evolved to use anatomy and imaging information to aid management and prognosis. However, classification systems lack reliability and validity data and are not specific to individual hamstring muscles, potentially missing parameters vital for sport-specific and activity-specific decision making. A narrative evidence review was conducted followed by a modified Delphi study to build an international consensus on best-practice decision-making for the classification of hamstring injuries. This comprised a digital information gathering survey to a cohort of 46 international hamstring experts (sports medicine physicians, physiotherapists, surgeons, trainers and sports scientists) who were also invited to a face-to-face consensus group meeting in London . Fifteen of these expert clinicians attended to synthesise and refine statements around the management of hamstring injury. A second digital survey was sent to a wider group of 112 international experts. Acceptance was set at 70% agreement. Rounds 1 and 2 survey response rates were 35/46 (76%) and 99/112 (88.4%) of experts responding. Most commonly, experts used the British Athletics Muscle Injury Classification (BAMIC) (58%), Munich (12%) and Barcelona (6%) classification systems for hamstring injury. Issues identified to advance imaging classifications systems include: detailing individual hamstring muscles, establishing optimal use of imaging in diagnosis and classification, and testing the validity and reliability of classification systems. The most used hamstring injury classification system is the BAMIC. This consensus panel recommends hamstring injury classification systems evolve to integrate imaging and clinical parameters around: individual muscles, injury mechanism, sporting demand, functional criteria and patient-reported outcome measures. More research is needed on surgical referral and effectiveness criteria, and validity and reliability of classification systems to guide management.
Diabetes patient preferences for glucose-monitoring technologies: results from a discrete choice experiment in Poland and the Netherlands
Authors: Smith Ian P , Whichello Chiara L , Veldwijk Jorien , Rutten-van Mölken Maureen P M H , Groothuis-Oudshoorn C G M , Vos Rimke C , de Bekker-Grob Esther W , de Wit G Ardine
Published: January 2023

Introduction

New glucose-monitoring technologies have different cost–benefit profiles compared with traditional finger-prick tests, resulting in a preference-sensitive situation for patients. This study aimed to assess the relative value adults with diabetes assign to device attributes in two countries.

Research design and methods

Adults with type 1 or 2 diabetes from the Netherlands (n=226) and Poland (n=261) completed an online discrete choice experiment. Respondents choose between hypothetical glucose monitors described using seven attributes: precision, effort to check, number of finger pricks required, risk of skin irritation, information provided, alarm function and out-of-pocket costs. Panel mixed logit models were used to determine attribute relative importance and to calculate expected uptake rates and willingness to pay (WTP).

Results

The most important attribute for both countries was monthly out-of-pocket costs. Polish respondents were more likely than Dutch respondents to choose a glucose-monitoring device over a standard finger prick and had higher WTP for a device. Dutch respondents had higher WTP for device improvements in an effort to check and reduce the number of finger pricks a device requires.

Conclusion

Costs are the primary concern of patients in both countries when choosing a glucose monitor and would likely hamper real-world uptake. The costs-benefit profiles of such devices should be critically reviewed.