bluuebunny/crossref_metadata_2025 huggingface dataset:
Intellectual disability healthcare in Australia: Progress, challenges, and future directions
Authors: Brooker K. S. , De Greef R. , Trollor J. N. , Franklin C. S. , Weise J.
Published: March 2024

People with intellectual disability experience some of the greatest health disparities in Australia. Individuals are expected to access mainstream health services that are ill equipped to meet their needs. The Australian government has made recent commitments to improve the healthcare of people with intellectual disability. This article describes the Australian health system and how it responds to the needs of people with intellectual disability. It draws on examples of advances in policy, inclusion, and service development, achieved through concrete and persistent systemic advocacy, to discuss emerging evidence on the delivery of healthcare to people with intellectual disability in Australia. The article also highlights immediate priorities including increasing the uptake of health assessments, building the capacity of our health workforce, and responding to the needs of people with intellectual disability in COVID‐19 outbreaks or other natural disasters. Intellectual disability healthcare is at a dynamic point in Australia with commitment and funding from government to lead to change. It is critical that momentum in health services development is maintained to enable improved health outcomes for people with intellectual disability.
Identification of two key genes involved in flavonoid catabolism and their different roles in apple resistance to biotic stresses
Authors: Zhao Qian , Li Xiaoning , Jiao Yu , Chen Ying , Yan Yanfang , Wang Yuzhu , Hamiaux Cyril , Wang Yule , Ma Fengwang , Atkinson Ross G. , Li Pengmin
Published: March 2024

Biosynthesis of flavonoid aglycones and glycosides is well established. However, key genes involved in their catabolism are poorly understood, even though the products of hydrolysis and oxidation play important roles in plant resistance to biotic stress.

Here, we report on catabolism of dihydrochalcones (DHCs), the most abundant flavonoids in domesticated apple and wild Malus. Two key genes, BGLU13.1 and PPO05, were identified by activity‐directed protein purification. BGLU13.1‐A hydrolyzed phlorizin, (the most abundant DHC in domesticated apple) to produce phloretin which was then oxidized by PPO05. The process differed in some wild Malus, where trilobatin (a positional isomer of phlorizin) was mainly oxidized by PPO05.

The effects of DHC catabolism on apple resistance to biotic stresses was investigated using transgenic plants. Either directly or indirectly, phlorizin hydrolysis affected resistance to the phytophagous pest two‐spotted spider mite, while oxidation of trilobatin was involved in resistance to the biotrophic fungus Podosphaera leucotricha. DHC catabolism did not affect apple resistance to necrotrophic pathogens Valsa mali and Erwinia amylovara.

These results suggest that different DHC catabolism pathways play different roles in apple resistance to biotic stresses. The role of DHC catabolism on apple resistance appeared closely related to the mode of invasion/damage used by pathogen/pest.
Maize functional requirements drive the selection of rhizobacteria under long‐term fertilization practices
Authors: Zhang Liyu , Yuan Liang , Wen Yanchen , Zhang Meiling , Huang Shuyu , Wang Shiyu , Zhao Yuanzheng , Hao Xiangxiang , Li Lujun , Gao Qiang , Wang Yin , Zhang Shuiqing , Huang Shaomin , Liu Kailou , Yu Xichu , Li Dongchu , Xu Jiukai , Zhao Bingqiang , Zhang Lu , Zhang Huimin , Zhou Wei , Ai Chao
Published: March 2024

Rhizosphere microbiomes are pivotal for crop fitness, but the principles underlying microbial assembly during root–soil interactions across soils with different nutrient statuses remain elusive.

We examined the microbiomes in the rhizosphere and bulk soils of maize plants grown under six long‐term (≥ 29 yr) fertilization experiments in three soil types across middle temperate to subtropical zones.

The assembly of rhizosphere microbial communities was primarily driven by deterministic processes. Plant selection interacted with soil types and fertilization regimes to shape the structure and function of rhizosphere microbiomes. Predictive functional profiling showed that, to adapt to nutrient‐deficient conditions, maize recruited more rhizobacteria involved in nutrient availability from bulk soil, although these functions were performed by different species. Metagenomic analyses confirmed that the number of significantly enriched Kyoto Encyclopedia of Genes and Genomes Orthology functional categories in the rhizosphere microbial community was significantly higher without fertilization than with fertilization. Notably, some key genes involved in carbon, nitrogen, and phosphorus cycling and purine metabolism were dominantly enriched in the rhizosphere soil without fertilizer input.

In conclusion, our results show that maize selects microbes at the root–soil interface based on microbial functional traits beneficial to its own performance, rather than selecting particular species.
Connectivity Constraints Ensuring Continuous Electrodes in Topology Optimization of Electroactive Polymer
Authors: Hård Daniel , Wallin Mathias , Ristinmaa Matti
Published: March 2024

Electroactive polymers (EAPs) deform when subject to an electric field, which is generated by two or more electrodes. To ensure proper function of the EAP, these electrodes are connected to a source and they are therefore required to be continuous such that no isolated islands exist. Increasing an EAP’s performance using topology optimization while ensuring electrode connectivity is the goal of this work. A topology optimization formulation is introduced where electrode connectivity is ensured using the virtual temperature method. Numerical experiments demonstrate that this is an efficient method to guarantee connectivity.
The episodic encoding of spoken words in Hindi
Authors: Clapp William , Sumner Meghan
Published: March 2024

The discovery that listeners more accurately identify words repeated in the same voice than in a different voice has had an enormous influence on models of representation and speech perception. Widely replicated in English, we understand little about whether and how this effect generalizes across languages. In a continuous recognition memory study with Hindi speakers and listeners (N = 178), we replicated the talker-specificity effect for accuracy-based measures (hit rate and D′), and found the latency advantage to be marginal (p = 0.06). These data help us better understand talker-specificity effects cross-linguistically and highlight the importance of expanding work to less studied languages.
The influence of the reference level on loudness and preference judgements for spectrally manipulated fan sounds
Authors: Claaßen Eike , Töpken Stephan , van de Par Steven
Published: March 2024

Fan sounds are often quantified using A-weighted sound pressure levels, silently acknowledging their limitations to fully capture the perceived unpleasantness. To overcome this limitation, level adjustments are a way to quantify the subjective preference of spectrally different sounds in listening experiments by adjusting the level of a test sound until it is equally preferred to a fixed reference sound. Since equal loudness contours differ, depending on the overall level, level adjustments might vary for different levels of the reference sound. This study aims to quantify the effects of spectral manipulations on level adjustments for loudness and preference judgements at reference sound pressure levels of either 45, 60, or 75 dB(A). Level adjustments of up to 12 dB were measured to make the stimuli equally preferred to the reference, particularly for sounds with prominent high-frequency components. The loudness and preference judgements were closely linked with each other, but an offset of about 3.5 dB at a reference level of 45 dB(A) indicates that equal loudness is not synonymous with equal preference. A linear regression model to predict level adjustments based on the reference level and an index reflecting the ratio of mid- to high-frequency loudness explains 73% of the variance.
Concentration of reflected sound in a room treated with cube corner retroreflectors
Authors: Cabrera Densil , Holmes Jonothan , Lu Shuai
Published: March 2024

A room was treated to be predominantly retroreflective in the high frequency range by introducing arrays of cube corner retroreflectors (CCRs) over most surfaces (excluding the floor). In a small room (volume 55 m3), 156 CCRs in the form of square trihedra with 350 mm edge lengths were used as wall and ceiling treatment. The horizontal plane distribution of reflected energy was measured from omnidirectional sources, and a head and torso simulator was used to measure voice support. Results show a high concentration of reflected energy returned to omnidirectional source positions in high frequency octave bands (2–8 kHz). Finite-difference time-domain (FDTD) simulations of the room yielded similar distributions to the omnidirectional measurements, showing greater sound concentration when more CCRs are introduced. By contrast, FDTD simulation of an equivalent flat-surfaced room yielded no reflected sound concentration at the source, with results close to diffuse field theory in high frequency octave bands. Measured voice support values derived from oral-binaural room impulse responses exceed diffuse theory expectations by 5 dB. Thus, the paper demonstrates that retroreflective array treatment can change room acoustical conditions, concentrating reflected energy onto an arbitrarily located source.
Integrative processing in artificial and biological vision predicts the perceived beauty of natural images
Authors: Nara Sanjeev , Kaiser Daniel
Published: March 2024

Previous research shows that the beauty of natural images is already determined during perceptual analysis. However, it is unclear which perceptual computations give rise to the perception of beauty. Here, we tested whether perceived beauty is predicted by spatial integration across an image, a perceptual computation that reduces processing demands by aggregating image parts into more efficient representations of the whole. We quantified integrative processing in an artificial deep neural network model, where the degree of integration was determined by the amount of deviation between activations for the whole image and its constituent parts. This quantification of integration predicted beauty ratings for natural images across four studies with different stimuli and designs. In a complementary functional magnetic resonance imaging study, we show that integrative processing in human visual cortex similarly predicts perceived beauty. Together, our results establish integration as a computational principle that facilitates perceptual analysis and thereby mediates the perception of beauty.
Ergodicity breaking from Rydberg clusters in a driven-dissipative many-body system
Authors: Ding Dongsheng , Bai Zhengyang , Liu Zongkai , Shi Baosen , Guo Guangcan , Li Weibin , Adams C. Stuart
Published: March 2024

It is challenging to probe ergodicity breaking trends of a quantum many-body system when dissipation inevitably damages quantum coherence originated from coherent coupling and dispersive two-body interactions. Rydberg atoms provide a test bed to detect emergent exotic many-body phases and nonergodic dynamics where the strong Rydberg atom interaction competes with and overtakes dissipative effects even at room temperature. Here, we report experimental evidence of a transition from ergodic toward ergodic breaking dynamics in driven-dissipative Rydberg atomic gases. The broken ergodicity is featured by the long-time phase oscillation, which is attributed to the formation of Rydberg excitation clusters in limit cycle phases. The broken symmetry in the limit cycle is a direct manifestation of many-body collective effects, which is verified experimentally by tuning atomic densities. The reported result reveals that Rydberg many-body systems are a promising candidate to probe ergodicity breaking dynamics, such as limit cycles, and enable the benchmark of nonequilibrium phase transition.
Flip the switch: the role of FleQ in modulating the transition between the free-living and sessile mode of growth in
Pseudomonas aeruginosa
Authors: Oladosu Victoria I. , Park Soyoung , Sauer Karin
Published: March 2024

Pseudomonas aeruginosa
is a Gram-negative, opportunistic pathogen causing chronic infections that are associated with the sessile/biofilm mode of growth rather than the free-living/planktonic mode of growth. The transcriptional regulator FleQ contributes to both modes of growth by functioning both as an activator and repressor and inversely regulating flagella genes associated with the planktonic mode of growth and genes contributing to the biofilm mode of growth. Here, we review findings that enhance our understanding of the molecular mechanism by which FleQ enables the transition between the two modes of growth. We also explore recent advances in the mechanism of action of FleQ to both activate and repress gene expression from a single promoter. Emphasis will be on the role of sigma factors, cyclic di-GMP, and the transcriptional regulator AmrZ in inversely regulating flagella and biofilm-associated genes and converting FleQ from a repressor to an activator.
Structure-guided mutagenesis of Henipavirus receptor-binding proteins reveals molecular determinants of receptor usage and antibody-binding epitopes
Authors: Oguntuyo Kasopefoluwa Y. , Haas Griffin D. , Azarm Kristopher D. , Stevens Christian S. , Brambilla Luca , Kowdle Shreyas S. , Avanzato Victoria A. , Pryce Rhys , Freiberg Alexander N. , Bowden Thomas A. , Lee Benhur
Published: March 2024

Nipah virus (NiV) is a highly lethal, zoonotic Henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans. Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor-binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner. NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors. Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, uses EFNB2 but not EFNB3. In this study, we employ a structure-informed approach to identify receptor-interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage. We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles. Further analyses uncovered two-point mutations (
NiV
N557S
GhV
and
NiV
Y581T
GhV
) pivotal for this phenotype. Moreover, we identify NiV interaction with Y120 of EFNB3 as important for the usage of this receptor. Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, confirm the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV- and NiV-specific monoclonal antibodies. Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveal regions critical for GhV binding of EFNB2, and describe putative HNV antibody-binding epitopes.

IMPORTANCE

Hendra virus and Nipah virus (NiV) are lethal, zoonotic Henipaviruses (HNVs) that cause respiratory and neurological clinical features in humans. Since their initial outbreaks in the 1990s, several novel HNVs have been discovered worldwide, including Ghana virus. Additionally, there is serological evidence of zoonotic transmission, lending way to concerns about future outbreaks. HNV infection of cells is mediated by the receptor-binding protein (RBP) and the Fusion protein (F). The work presented here identifies NiV RBP amino acids important for the usage of ephrin-B3 (EFNB3), a receptor highly expressed in neurons and predicted to be important for neurological clinical features caused by NiV. This study also characterizes epitopes recognized by antibodies against divergent HNV RBPs. Together, this sheds insight to amino acids critical for HNV receptor usage and antibody binding, which is valuable for future studies investigating determinants of viral pathogenesis and developing antibody therapies.
Complete genome sequence of
Methanosphaera
sp. ISO3-F5, a rumen methylotrophic methanogen
Authors: Palevich Nikola , Jeyanathan Jeyamalar , Reilly Kerri , Palevich Faith P. , Maclean Paul H. , Li Dong , Altermann Eric , Kelly William J. , Leahy Sinead C. , Attwood Graeme T. , Ronimus Ron S. , Henderson Gemma , Janssen Peter H.
Published: March 2024

Methanosphaera
spp. are methylotrophic methanogenic archaea and members of the order Methanobacteriales with few cultured representatives.
Methanosphaera
sp. ISO3-F5 was isolated from sheep rumen contents in New Zealand. Here, we report its complete genome, consisting of a large chromosome and a megaplasmid (GenBank accession numbers
CP118753
and
CP118754
, respectively).
Management of recurrent pinna haematoma following rugby injury: a surgical approach
Authors: Hu Haiyang , Hulse Kate , Iyer Arunachalam
Published: March 2024

A young adult male developed a left-sided pinna haematoma after a rugby injury. The haematoma reaccumulated after multiple attempts at drainage under local anaesthetic in emergency rooms and required incision and drainage in the theatre under general anaesthetic. Intraoperatively, multiple venous bleeding points were identified and these were controlled with bipolar diathermy. The wound was closed and dressed with bolster and crepe bandage. On day 7 postoperatively, the sutures and dressings were removed and the haematoma had not recurred. He returned to playing rugby on day 21 postoperatively and sustained another blunt impact to his left ear. He noticed new swelling over the posterior aspect of the same ear. This was drained via needle aspiration and there was no further reaccumulation of the pinna haematoma.
When I use a word . . . Medical blue plaques—the Peckham Experiment
Authors: Aronson Jeffrey K
Published: March 2024

The Pioneer Health Centre in Peckham, also known as the Peckham Centre, running what became known at the Peckham Experiment, was founded in 1926 by two doctors, Innes Pearse (1889–1978) and her colleague George Scott Williamson (1884–1953). It closed down in 1929 and reopened in 1935 in new purpose-built premises. Families paid a shilling a week for membership, which gave them free medical consultations of various sorts and access to a wide variety of recreations, but no medical treatment. The purpose was to observe how their health progressed and to discover what factors were involved in good health and wellbeing. After closing down again during World War II the centre reopened, but was forced to close again in 1950, this time for good, because of lack of funds, due to a complex range of factors. In a 1938 publication, the founders stressed that health and wellbeing were not synonymous; health, they wrote, operates with a cumulative deposit account and wellbeing on a diminishing current account. Two blue plaques commemorate the Pioneer Health Centre: an English Heritage blue plaque at 142 Queen’s Road, Peckham, London SE15, the site of the centre’s original building, and a plaque put up by the London Borough of Southwark at the site of the second building, now converted to a block of flats, and situated round the corner from the Queen’s Road premises, in Frobisher Place, St Mary’s Road, Peckham.
Methadone as an adjuvant analgesic
Authors: Shahab Julita , Willis Derek
Published: March 2024

Methadone as an 'adjuvant' has proven to be effective and safe to be used in conjunction with opioids. Generally, only a low dose is required to improve pain control.
Geriatric screening and comprehensive geriatric assessment during initial oncology appointments
Authors: Madureira Tânia , Magalhães Joana , Vilas Pedro , Campôa Elsa , Luz Paulo , Coutinho Filipe
Published: March 2024

Introduction

Geriatric oncology underscores the significance of assessing functional age in guiding medical decisions, endeavouring to delineate practical and efficacious methodologies for evaluating functionality, adapting therapeutic regimens and attenuating the risks of treatment-related deterioration.

Objectives and Methods

In this prospective study, we aimed to delineate the characteristics of older patients presenting for their initial oncology appointment by using geriatric screening (G8 score) and comprehensive geriatric assessment (CGA), while also assessing the feasibility of these evaluations. Secondary objectives included comparing the initial Eastern Cooperative Oncology Group (ECOG) performance status and any deviations from standard therapeutic strategies against the identified frailty in geriatric assessment.

Results

Most patients exhibited a G8 score ≤14 and underwent comprehensive geriatric assessment. While oncologists typically perceive patients’ general conditions, CGA enables a systematic assessment, providing a comprehensive characterisation of elderly patients to inform therapeutic decisions and address identified fragilities. The CGA highlighted vulnerabilities across all primary domains. Notably, even among patients with ECOG scores of 0 and 1, the application of G8 score and CGA revealed numerous fragilities. Consistent with existing literature, these scales offered additional insights beyond ECOG evaluation alone, suggesting their potential to guide therapeutic adaptations for this demographic.

Conclusion

Ongoing research and continuous evaluation are imperative to refine and broaden the implementation of geriatric-focused interventions.
Finite element modeling of the rotational dynamics of a single magnetic particle in a strong magnetic field and liquid medium
Authors: Krafcik Andrej , Frollo Ivan , Strbak Oliver , Babinec Peter
Published: March 2024

We have performed a comparative computational study of magnetic particle alignment in a strong magnetic field and ambient viscous fluid using the first-principles Navier–Stokes equation as well as numerical modeling using the finite element method (FEM). FEM solution has been compared with the solution of the unsteady rotations of a magnetic particle in a viscous fluid during the alignment process described with nonlocal integro-differential equations (IDEs) for torque and angular velocity. The assumption of nonlocality comes from the history term of acceleration torque with a non-Basset kernel function, which has its origin in the presence of vortices in the flow of a particle fluid environment due to its unsteady rotation and ambient fluid inertia and friction. The flow vortices of the ambient fluid are explicitly shown in the solution of the FEM model. Moreover, the solution of the time evolution of the alignment angle and angular velocity for the FEM model are in good agreement with an IDE model which we have recently developed. The obtained results are justification for interchangeability of the FEM and IDE models, which may have important consequences for large-scale simulations of magnetic microparticles.
Label-Free Optical Technologies to Enhance Noninvasive Endoscopic Imaging of Early-Stage Cancers
Authors: Chang Shuang , Krzyzanowska Halina , Bowden Audrey K.
Published: March 2024

White light endoscopic imaging allows for the examination of internal human organs and is essential in the detection and treatment of early-stage cancers. To facilitate diagnosis of precancerous changes and early-stage cancers, label-free optical technologies that provide enhanced malignancy-specific contrast and depth information have been extensively researched. The rapid development of technology in the past two decades has enabled integration of these optical technologies into clinical endoscopy. In recent years, the significant advantages of using these adjunct optical devices have been shown, suggesting readiness for clinical translation. In this review, we provide an overview of the working principles and miniaturization considerations and summarize the clinical and preclinical demonstrations of several such techniques for early-stage cancer detection. We also offer an outlook for the integration of multiple technologies and the use of computer-aided diagnosis in clinical endoscopy.
Understanding Organic Photovoltaic Materials Using Simple Thermal Analysis Methodologies
Authors: Khirbat Aditi , Nahor Oded , Marina Barbier Sara , Levitsky Artem , Martín Jaime , Frey Gitti , Stingelin Natalie
Published: March 2024

Large strides have been made in designing an ever-increasing set of modern organic materials of high functionality and thus, often, of high complexity, including semiconducting polymers, organic ferroelectrics, light-emitting small molecules, and beyond. Here, we review how broadly applied thermal analysis methodologies, especially differential scanning calorimetry, can be utilized to provide unique information on the assembly and solid-state structure of this extensive class of materials, as well as the phase behavior of intrinsically intricate multicomponent systems. Indeed, highly relevant insights can be gained that are useful, e.g., for further materials-discovery activities and the establishment of reliable processing protocols, in particular if combined with X-ray diffraction techniques, spectroscopic tools, and scanning electron microscopy enabled by vapor-phase infiltration staining. We, hence, illustrate that insights far richer than simple melting point– and glass-transition identification can be obtained with differential scanning calorimetry, rendering it a critical methodology to understand complex matter, including functional macromolecules and blends.
Brachyury promotes extracellular matrix synthesis through transcriptional regulation of Smad3 in nucleus pulposus
Authors: Xia Yanzhang , Wu Yinghui , Gong Yuhao , Yue Caichun , Tao Linfeng , Xin Tianwen , Shen Cong , Zhu Yue , Shen Minghong , Shen Jun
Published: March 2024

Mechanically, in the nucleus, Bry enhances the transcription of Smad3, leading to increased expression of Smad3 protein levels; in the cytoplasm, elevated substrate levels further lead to an increase in the phosphorylation of Smad3, thereby regulating collagen II and aggrecan expression. Further in vivo experiments provide additional evidence that Bry can alleviate IVDD through this mechanism.
GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage
Authors: Park Brady , Bakbak Ehab , Teoh Hwee , Krishnaraj Aishwarya , Dennis Fallon , Quan Adrian , Rotstein Ori D. , Butler Javed , Hess David A. , Verma Subodh
Published: March 2024

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.
Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients
Authors: Ebrahimian Serajeddin , Sillanmäki Saara , Hietakoste Salla , Kulkas Antti , Töyräs Juha , Bailón Raquel , Hernando David , Lombardi Carolina , Grote Ludger , Bonsignore Maria R. , Saaresranta Tarja , Pépin Jean-Louis , Leppänen Timo , Kainulainen Samu
Published: March 2024

Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.
Exploring the Security Vulnerability in Frequency-Hiding Order-Preserving Encryption
Authors: Yang JiHye , Kim Kee Sung
Published: March 2024

Frequency-hiding order-preserving encryption (FH-OPE) has emerged as an important tool in data security, particularly in cloud computing, because of its unique ability to preserve the order of plaintexts in their corresponding ciphertexts and enable efficient range queries on encrypted data. Despite its strong security model, indistinguishability under frequency analyzing ordered chosen plaintext attack (IND-FA-OCPA), our research identifies a vulnerability in its design, particularly the impact of range queries. In our research, we quantify the frequency of data exposure resulting from these range queries and present potential inference attacks on the FH-OPE scheme. Our findings are substantiated through experiments on real-world datasets, with the goal of measuring the frequency of data exposure resulting from range queries on FH-OPE encrypted databases. These results quantify the level of risk in practical applications of FH-OPE and reveal the potential for additional inference attacks and the urgency of addressing these threats. Consequently, our research highlights the need for a more comprehensive security model that considers the potential risks associated with range queries and underscores the importance of developing new range-query methods that prevent exposing these vulnerabilities.
The Effect of a Combination of Vibration and External Cold on Pain Caused during Vaccine Injection in Infants: A Randomized Clinical Trial
Authors: Unesi Zahra , Amouzeshi Zahra , Jamavar Javad , Mahmoudzadeh Zarandi Fatemeh
Published: March 2024

Aim. This study was conducted to determine the effect of combining vibration and external cold on pain caused by vaccine injection among six-month-old infants. Design. Randomized controlled trial. Methods. In this clinical trial, 80 eligible infants were selected from the infants referred to a health center as per the inclusion criteria. The infants were assigned to either a control group or an intervention group by block randomization. In the intervention group, a vibrating and cold device was placed above the injection site from one minute before to 15 seconds after the pentavalent vaccine injection. In the control group, no intervention was performed, and they were vaccinated according to the routine procedure. The pain status in the two groups was measured using the Modified Behavioral Pain Scale (MBPS) 15 seconds after the injection, and the crying duration was assessed from the injection of the vaccine till the end of it. Data were analyzed in SPSS 23 software using Mann–Whitney, t, Spearman, and chi-square tests. The level of significance was set to p<0.05. Results. Most participants in the control (55%) and intervention (55%) groups were girls. Statistical data analysis of 80 infants showed that the mean pain intensity (p=0.032) and duration of crying (p=0.0001) in the intervention group (6.1 ± 1.8, 32.47 ± 16.78) were lower than those of the control group (7.2 ± 0.1, 51.02 ± 25.9), respectively. Conclusion. Because the intensity of pain, especially the duration of crying, was lower in the intervention group than in the control group, we may suggest that nurses use simple pain relief solutions in vaccination centers, such as a combination of vibration and cold. This trial is registered with IRCT201207157130N2.
Fig. S5 from Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity
Authors: Li Xuefeng , Huntoon Kristin , Wang Yifan , Lee DaeYong , Dong Shiyan , Antony Abin , Walkey Carl , Kim Betty Y.S. , Jiang Wen
Published: March 2024

Fig. S5
Abstract A036: Female spouse caregivers of patients with glioblastoma want better education and communication from health care professionals regarding what to expect during the disease progression
Authors: Coman Diana L. , Chard Megan P. , Lutz Barbara J. , Minns Laurie A.
Published: March 2024

The purpose of this study was to understand the challenges and unmet needs of primary spousal caregivers of patients with glioblastoma multiforme (GBM) through a qualitative analysis of letters written by current and former caregivers. GBM is a devastating and terminal cancer that results in memory loss, cognitive declines, personality changes, neuropsychiatric symptoms, and physical impairments that greatly affect quality of life of both the patient with GBM and their primary caregiver, who is often a spouse or partner. Open-ended letters (n=101) written by self-identified female spouse caregivers were analyzed using reflexive thematic analysis (IRB #22-0103). The six phases of reflexive thematic analysis involved 1) data familiarization, 2) systematic data coding, 3) generation of initial themes, 4) development and reviewing themes, 5) refinement and re-naming of themes and 6) writing the report to provide insight into caregiver’s experience. Seven distinct themes were identified from the letters. Three of the themes related to the patient experiences: 1) medical details of the disease trajectory (87%), 2) interactions of the patient/caregiver dyad with health care workers (67%), and 3) the changing patient condition over time (98%). Four themes focused on the caregiver experience: 1) caregiver challenges (80%), 2) caregiver responses (77%), 3) caregiver coping strategies (85%), and description of tangible needs that would help other caregivers in the future (91%). When mapped to the four phases of the caregiving trajectory: acute disease phase, living with disease progression, end of life phase, and the bereavement phase, caregivers needed better communication and support in every phase. The highest caregiver needs were for better education about GBM from health care professionals regarding what to expect and better communication with health care providers about disease progression, treatment options, and anticipated patient, caregiver, and family needs (65%). Caregivers indicated they wanted to be listened to and included in medical decision-making. These findings on the primary caregivers’ experiences provide opportunities to guide more timely and tailored interventions to provide support and improve care for patient/caregiver dyads to help mitigate the burden of this progressive disease and improve quality of life for caregivers and their patients with GBM.

Citation Format: Diana L. Coman, Megan P. Chard, Barbara J. Lutz, Laurie A. Minns. Female spouse caregivers of patients with glioblastoma want better education and communication from health care professionals regarding what to expect during the disease progression [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A036.
Abstract A046: Exogenous CD200 suppressing T cells is CD200R1 independent
Authors: Xiong Zhengming , Olin Micheal R.
Published: March 2024

As one of immune checkpoint blockade, CD200 is widely considered to exert immunosuppressive and inflammatory suppressive functions through receptors on its immune cell membrane (1,2,3). Unlike the widespread use of anti-PD-1, few successful studies have been reported in the use of anti-CD200/CD200R in anti-tumor immunotherapy researches. This makes it necessary to re-understand the mechanism of action and biological effects of CD200 protein. We studied antigen-presenting cells and T cells in an environment where CD200R1 knockout macrophages and wild-type macrophages interact with antigen-specific T cells, respectively, and in vitro in human PBMCs using synthetic CD200 membrane segments. Changes in immune function and gene expression in signaling pathways is also involved. The experimental results show that comparing with inactivated human PBMC, CD200-Fc fusion protein significantly inhibited the division of human PBMC cells activated by ConA (Fig 1). Further experiments showed that the recombinant CD200 extracellular domain has a positive inhibitory effect on IL6, TNF and IL17A produced from PBMCs activated by PMA + ionomycin but has no effect on the production of IFNr. The recombinant CD200 extracellular domain itself can induce a large amount of IL6. (Fig.2). In view of the close relationship between IFNr and antigen-TCR function, we speculate that CD200 protein has no direct relationship with immunosuppression of antigen-specific T cells. To this end, we performed the following experiments. When CD200 plus gp100 antigen polypeptide acted on only CD200R1 knock out macrophages, cocultured gp100 antigen-specific CD3 T cells produced significantly less IFNr and TNF than only gp100 antigen polypeptide stimulation (IFNr 227.8pg/ml vs 803.2 pg/ml, p <0.01); TNF 3984pg/ml vs 5187pg/ml, p <0.0001). Moreover, when using CD200 plus gp100 antigen polypeptide as stimuli of the APC, IFNr and TNF production during T cells cocultured with the APCs are not significant different between the macrophage groups with and without CD200R1 gene (IFNr 161.8pg/ml vs 227.8 pg/ml p> 0.05; TNF 3715pg/ml vs 3984pg/ml, p> 0.05). This indicates that CD200R1 is not required for the immunosuppressive function of CD200 in relation with antigen. Secondly, IFNr produced by T cells induced by gp100 on CD200R1 knockout macrophages was significantly higher than that of wild-type macrophages (IFNr 803.2pg/ml vs 329.3pg/ml, p<0.01), which indicates that inactivated CD200R1 itself has positively regulated the activity of the antigen-TCR system. (Fig.4) In short, exogenous CD200 induces immunosuppression of antigen-specific T cells through a CD200R1-independent mechanism.

Citation Format: Zhengming Xiong, Micheal R. Olin. Exogenous CD200 suppressing T cells is CD200R1 independent [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A046.
Abstract A051: Treatment outcome of leptomeningeal metastasis from breast cancer
Authors: Kim Suzy , Lee Choong-won
Published: March 2024

Purpose: Leptomeningeal metastasis (LM) is well-known for its dismal prognosis. Despite various treatment approaches, there has been minimal improvement in survival, and the optimal treatment for leptomeningeal metastasis remains uncertain. Our study aimed to report treatment outcomes using different modalities for LM and to identify prognostic factors. Materials and Methods: We analyzed 111 breast cancer patients with LM, who were treated at Seoul National University and Seoul Metropolitan Government Seoul National University Boramae Medical Center between January 2010 and December 2022. The median follow-up period was 4.4 months (range, 0.2 – 125.4 months). Results: The median age was 48 years, with the majority having a Karnofsky performance status below 60 (n = 100, 90.1%). Among the 111 patients, intrathecal chemotherapy was the most commonly used treatment modality (n = 89, 80.2%), followed by radiotherapy (n = 74, 66.7%), and systemic chemotherapy (n = 56, 50.5%). The median freedom from progression was 3.4 months. In multivariate analysis, patients who underwent more than 2 treatment modalities experienced significantly longer progression-free interval (1.8 months vs. 7.4 months, HR = 0.20, p = 0.038). Additionally, patients who underwent excision of the primary breast tumor displayed a tendency for longer progression-free interval (3.1 months vs. 3.4 months, HR = 0.33, p = 0.084). Patients with systemic inflammation index greater than 500 × 103/mm3 at the time of the diagnosis of LM exhibited shorter progression-free interval (3.5 months vs. 2.9 months, HR = 2.88, p = 0.056). There was no difference of progression-free interval according to treatment modalities. Conclusions: The freedom from progression of LM originating from breast cancer was found to be poor, exhibiting less than 4 months. A multimodal approach upon LM and high systemic inflammation index at the time of the diagnosis of LM demonstrated significant difference in prognosis. Further research is warranted to elucidate the clinical implications and develop optimized treatment strategie

Citation Format: Suzy Kim, Choong-won Lee. Treatment outcome of leptomeningeal metastasis from breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A051.
Abstract B046: Irradiation of patient-derived high-grade gliomas reduces 5-ALA-induced fluorescence utility during re-resection
Authors: Minhas Paras S. , Durairaj Aarooran , McReynolds Melanie , Andreasson Katrin I. , Jung YooJin , Rabinowitz Joshua
Published: March 2024

High grade gliomas HGGs are among the most aggressive primary brain tumors, yielding a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat HGG’s poor prognosis. Recent studies have established that HGG cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived cell lines. Acute dosages of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), which is known to be converted into the fluorescent metabolite protoporphyrin IX (PpIX) in the porphyrin synthesis pathway. PpIX has been utilized by surgeons in fluorescence-guided tumor resection for clearer visualization of tumor boundaries in recent years. Fractionation of radiation therapy also resulted in dose-dependent changes in the pathway concerning heme synthesis within these cells, especially presenting decreased levels of ALA dehydratase (ALAD) and increased levels of ferrochelatase. As ALAD promotes PpIX accumulation and ferrochelatase catalyzes its conversion to heme, this indicates a decreased favorability for the accumulation of PpIX in the reprogrammed metabolism of HGG cells following radiation. Consequently, we propose that PpIX fluorescence is not a reliable visual aide in surgical re-resection of HGGs post-radiation therapy.

Citation Format: Paras S. Minhas, Aarooran Durairaj, Melanie McReynolds, Katrin I. Andreasson, YooJin Jung, Joshua Rabinowitz. Irradiation of patient-derived high-grade gliomas reduces 5-ALA-induced fluorescence utility during re-resection [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B046.
Abstract B051: DNA damage signaling activates GTP synthesis to promote glioblastoma treatment resistance
Authors: Scott Andrew J. , O'Brien Alexandra , Zhou Weihua , Xu Jie , Palavalasa Sravya , Kothari Ayesha U. , Wilder-Romans Kari , Zhang Li , Andren Anthony C. , Chandrasekaran Sriram , Heth Jason , Umemura Yoshie , Qi Nathan , Lawrence Theodore S. , Al-Holou Wajd N. , Lyssiotis Costas A. , Wahl Daniel R
Published: March 2024

Glioblastoma (GBM) is the most common type of invasive brain tumor in adults and is uniformly fatal due to inherent resistance to radiation therapy (RT) and chemotherapy. Our group and others have found that metabolites can regulate DNA repair and therapy resistance in brain tumors, but little is known about how DNA damage regulates metabolic pathway activity in cancer. Here we show that following treatment with RT, GBMs increase rates of de novo guanylate synthesis in vitro and in orthotopic patient-derived xenograft models via signaling through the DNA repair protein DNA-PK. To determine if disrupting this regulation can augment GBM treatment efficacy, we combined an FDA-approved inhibitor of purine synthesis (mycophenolate mofetil, MMF) with chemoradiation in a variety of mouse models of GBM. Critically, targeting GTP synthesis improved the efficacy of both RT alone and chemoradiation in multiple patient-derived and syngeneic intracranial models. Our translational studies have shown that mycophenolic acid, the active metabolite of MMF, penetrates the blood-brain barrier at concentrations sufficient to inhibit GTP synthesis in GBMs of human patients. The phase 1 arms of our study, which are ongoing, are testing the safety and efficacy of combining MMF with standard of care chemoradiation for patients with primary and recurrent GBM.

Citation Format: Andrew J. Scott, Alexandra O'Brien, Weihua Zhou, Jie Xu, Sravya Palavalasa, Ayesha U. Kothari, Kari Wilder-Romans, Li Zhang, Anthony C. Andren, Sriram Chandrasekaran, Jason Heth, Yoshie Umemura, Nathan Qi, Theodore S. Lawrence, Wajd N. Al-Holou, Costas A. Lyssiotis, Daniel R Wahl. DNA damage signaling activates GTP synthesis to promote glioblastoma treatment resistance [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B051.
Abstract A005: Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma
Authors: Nie Hao , Zhou Wei , Wang Chen , Zhang Nan , Wu Shuai , Zhang Rugang
Published: March 2024

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ~50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the alanine transporter SLC38A2 synergizes with immune checkpoint blockade (ICB) in ARID1A-inactivated OCCCs. Unbiased metabolic profiling revealed that alanine levels were increased by ARID1A inactivation in OCCC cells. In addition, using genome-wide approaches, we discovered that SWI/SNF inactivation downregulates SLC7A8 that is responsive for alanine secretion, while upregulating SLC38A2 that uptakes alanine extracellularly. This creates a dependence on the alanine consumption in ARID1A-inactivated cells. Inhibition of SLC38A2 reduces alanine uptake, impairs mitochondrial respiration, and induces cell cycle arrest and ARID1A inactivation exacerbates these effects. SLC38A2 inhibition suppresses the growth of ARID1A mutant, but not wildtype, OCCCs. In addition, SLC38A2 inhibition synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional ARID1A inactivation. Our data indicate that inhibition of the alanine metabolism simultaneously suppresses tumor cell growth and boosts antitumor immunity, which synergizes with immune checkpoint blockade in suppressing ARID1A-mutated cancers.

Citation Format: Hao Nie, Wei Zhou, Chen Wang, Nan Zhang, Shuai Wu, Rugang Zhang. Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A005.