bluuebunny/crossref_metadata_2025 huggingface dataset:
Conditional PROTAC: Recent Strategies for Modulating Targeted Protein Degradation
Authors: Yim Junhyeong , Park Junyoung , Kim Gabin , Lee Hyung Ho , Chung Jin Soo , Jo Ala , Koh Minseob , Park Jongmin
Published: July 2024

Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin‐proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and the wide‐range of applications across diverse disease contexts, off‐tissue effects and side‐effects of PROTACs have recently received attentions to improve their efficacy. To address these issues, spatial or temporal target protein degradation by PROTACs has been spotlighted. In this review, we explore chemical strategies for modulating protein degradation in a cell type‐specific (spatio−) and time‐specific (temporal−) manner, thereby offering insights for expanding PROTAC applications to overcome the current limitations of target protein degradation strategy.
Orbi‐SIMS Mediated Metabolomics Analysis of Pathogenic Tissue up to Cellular Resolution
Authors: Kern Christine , Scherer Astrid , Gambs Laura , Yuneva Mariia , Walczak Henning , Liccardi Gianmaria , Saggau Julia , Kreuzaler Peter , Rohnke Marcus
Published: July 2024

Tumors have a complex metabolism that differs from most metabolic processes in healthy tissues. It is highly dynamic and driven by the tumor cells themselves, as well as by the non‐transformed stromal infiltrates and immune components. Each of these cell populations has a distinct metabolism that depends on both their cellular state and the availability of nutrients. Consequently, to fully understand the individual metabolic states of all tumor‐forming cells, correlative mass spectrometric imaging (MSI) up to cellular resolution with minimal metabolite shift needs to be achieved. By using a secondary ion mass spectrometer (SIMS) equipped with an Orbitrap mass analyzer, we present a workflow to image primary murine tumor tissues up to cellular resolution and correlate these ion images with post acquisition immunofluorescence or histological staining. In a murine breast cancer model, we could identify metabolic profiles that clearly distinguish tumor tissue from stromal cells and immune infiltrates. We demonstrate the robustness of the classification by applying the same profiles to an independent murine model of lung cancer, which is accurately segmented by histological traits. Our pipeline allows metabolic segmentation with simultaneous cell identification, which in the future will enable the design of subpopulation‐targeted metabolic interventions for therapeutic purposes.
Computational biomechanics for a standing human body: Modal analysis and simulation
Authors: Chen Goong , Scully Matthew M. , Huang Jingtong , Sergeev Alexey , Yang Jing , Wei Chunqiu , Monday Patrick , Cohen Leon , Cheng Xingong , Liu Sanyang , Wang Junmin , Zhou Shuqin
Published: July 2024

We develop computational mechanical modeling and methods for the analysis and simulation of the motions of a human body. This type of work is crucial in many aspects of human life, ranging from comfort in riding, the motion of aged persons, sports performance and injuries, and many ergonomic issues. A prevailing approach for human motion studies is through lumped parameter models containing discrete masses for the parts of the human body with empirically determined spring, mass, damping coefficients. Such models have been effective to some extent; however, a much more faithful modeling method is to model the human body as it is, namely, as a continuum. We present this approach, and for comparison, we choose two digital CAD models of mannequins for a standing human body, one from the versatile software package LS‐DYNA and another from open resources with some of our own adaptations. Our basic view in this paper is to regard human motion as a perturbation and vibration from an equilibrium position which is upright standing. A linear elastodynamic model is chosen for modal analysis, but a full nonlinear viscoelastoplastic extension is possible for full‐body simulation. The motion and vibration of these two mannequin models is analyzed by modal analysis, where the normal vibration modes are determined. LS‐DYNA is used as the supercomputing and simulation platform. Four sets of low‐frequency modes are tabulated, discussed, visualized, and compared. Higher frequency modes are also selectively displayed. We have found that these modes of motion and vibration form intrinsic basic modes of biomechanical motion of the human body. This view is supported by our finding of the upright walking motion as a low‐frequency mode in modal analysis. Such a “walking mode” shows the in‐phase and out‐of‐phase movements between the legs and arms on the left and right sides of a human body, implying that this walking motion is spontaneous, likely not requiring any directives from the brain. Dynamic motions of CAD mannequins are also simulated by drop tests for comparisons and the validity of the models is discussed through Fourier frequency analysis. All computed modes of motion are collected in several sets of video animations for ease of visualization. Samples of LS‐DYNA computer codes are also included for possible use by other researchers.
Food Effect and Pharmacokinetic Bridging of Avacopan in Caucasian and Japanese Healthy Participants
Authors: Miao Shichang , Bekker Pirow , Armas Danielle , Lor Mary , Hanada Ryuzo , Okamura Shota , Umezawa Yuko , Trivedi Ashit
Published: July 2024

Avacopan 30 mg twice daily (BID) is approved for the treatment of severe active antineutrophil cytoplasmic autoantibody–associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). Food effect on avacopan pharmacokinetics (PKs) and PK bridging in Japanese participants were examined through 2 phase 1 studies involving healthy adult participants. In Study 1, an open‐label, crossover trial, participants received oral administration of a single 30‐mg dose of avacopan under fasted and fed conditions. Study 2 was a randomized, single‐blind, placebo‐controlled trial in Caucasian and Japanese participants: Part A investigated single doses of 10 and 30 mg of avacopan under fasted and fed conditions and Part B investigated 30 and 50 mg BID avacopan. The PKs of single‐dose administrations of 10 and 30 mg in Japanese participants was compared with that in Caucasian participants under fasted conditions. Food substantially increased plasma avacopan area under the plasma concentration‐time curve from time 0 to time infinity (AUC0‐inf) by 1.72‐fold, supporting the recommendation of taking avacopan with food. Maximum plasma concentration (Cmax) remained relatively unchanged. The median time to reach Cmax (tmax) was delayed by 3 hours. No significant food effect was observed on the active metabolite CCX168‐M1 (M1) AUC. Avacopan and M1 exposures were <1.5‐fold higher in Japanese participants than in Caucasian participants following multiple‐dose administration of avacopan.
Blockchain based secret key management for trusted platform module standard in reconfigurable platform
Authors: Paul Rourab , Ghosh Nimisha , Panigrahi Amrutanshu , Chakrabarti Amlan , Mohapatra Prasant
Published: July 2024

The growing sophistication of cyber attacks, vulnerabilities in high computing systems and increasing dependency on cryptography to protect our digital data, make it more important to keep secret keys safe and secure. A few major issues of secret keys, like incorrect use of keys, inappropriate storage of keys, inadequate protection of keys, insecure movement of keys, lack of audit logging, insider threats and nondestruction of keys can compromise the whole security system severely. In this work, we propose a field programmable gate array (FPGA)‐based trusted platform module (TPM) framework for operating system companies and OS users, utilizing blockchain to address NIST‐recommended secret key management issues. The security processor used in OS user machines is partitioned into three areas such that processor area, confidential area, and crypto area. The isolated secret key memory in confidential area, along with a private blockchain (BC) can log the life cycle of secret keys of TPM standard. We have also implemented a special custom bus interconnect, which receives custom crypto instructions from Processing Element (PE). During the execution of crypto instructions, the architecture ensures that secret keys are present in confidential area and crypto area but never in the processor area. The movements of secret keys between confidential area, and crypto area are recorded cryptographically after the proper authentication process controlled by the proposed hardware‐based private BC framework. To the best of our knowledge, this work is the first attempt to implement a blockchain‐based framework between OS company and OS users to address NIST recommended secret key management issues of TPM standard hardware environment. The additional cost of resource usage and timing complexity we spent to implement the proposed idea is nominal. The proposed architecture is implemented with Xilinx EDA tool using FPGA board.
Limitations Reported in Evaluating Effectiveness of Risk Minimization Measures in the EU during 2018–2021: A Qualitative Analysis of Industry‐Sponsored Post‐Authorization Safety Studies
Authors: Grupstra Renske J. , Goedecke Thomas , Gardarsdottir Helga
Published: July 2024

Marketing‐authorization holders evaluate the effectiveness of risk minimization measures (RMM) for medicines through the conduct of post‐authorization safety studies (PASS). Earlier studies show that concluding on RMM effectiveness is challenging. The aim of this study was to describe reported limitations associated with RMM effectiveness assessments of industry‐sponsored PASS that did not render a conclusion. We conducted a thematic analysis of study limitations extracted from assessment reports and study reports finalized by the Pharmacovigilance Risk Assessment Committee between 2018 and 2021. In 39 (61.0%) of the PASS a conclusion on RMM effectiveness was drawn, where 25 (39.0%) PASS was inconclusive. Most PASS had a cross‐sectional design with surveys as primary data sources (73.4% and 65.6% respectively). Four main themes emerged: (i) survey‐specific limitations, (ii) limitations specifically related to secondary use of data, (iii) general limitations related to study design, and (iv) limitations not related to study design. In general, frequently reported limitations were survey‐related, such as selection bias or information bias. Interestingly, well‐known study limitations related to secondary use of data such as missing or misclassification of data were more often presented in inconclusive compared with conclusive PASS. Given that about 40% of PASS did not allow a conclusion on RMM effectiveness, our results suggest prioritization for strategies to mitigate limitations related to the secondary use of data at the protocol stage, for example, through feasibility assessments. Although many databases may have incomplete registration of some variables, feasibility testing prior to conducting a PASS could contribute to meeting study objectives and concluding on RMM effectiveness.
A wide tuning range CMOS differential ring VCO using an active inductor for wireless applications
Authors: Alijani Mahdi , Javanmardi Mohammadmahdi , Abrishamifar Adib
Published: July 2024

A differential ring voltage‐controlled oscillator (DRVCO) is proposed in this paper as one of the critical blocks in communication systems. It consists of four stages of delay cells connected in a chain, creating a ring structure with auxiliary path interconnections. The oscillation frequency of the DRVCO can be controlled by adjusting the tuning voltage that controls the charging current. To achieve the desired performance for wireless applications, the Wu active inductor, which is a low‐noise and high‐quality factor active inductor, is employed in each delay cell for the first time. Using an active inductor provides a wide tuning range and also allows for proper phase noise and low power consumption. The proposed circuit is designed and simulated using standard 180‐nm CMOS technology with a 1.8‐V voltage source (VDD). The circuit is designed to achieve a tuning range of 2.15 GHz with a center frequency oscillation of 2.745 GHz, over the control voltage variation of 1.4 V (0 to 1.4 V). To achieve the desired performance, the circuit consumes an average power of 1.99 mW. It achieves a phase noise of − 91.2 dBc/Hz at 1 MHz offset frequency, indicating effective noise suppression. The figure of merit (FoM) for the circuit is − 156.9 dBc/Hz, representing its overall performance. The final layout of the circuit estimates an area of 0.00072 mm2. Various analyses, including Monte–Carlo simulations, PVT (process, voltage, temperature) variation analysis, and other relevant analyses, have been performed to ensure the reliable performance of the proposed circuit.
Identification of aryl hydrocarbon receptor allosteric antagonists from clinically approved drugs
Authors: Mosa Farag E. S. , Alqahtani Mohammed A. , El‐Ghiaty Mahmoud A. , Dyck Jason R. B. , Barakat Khaled , El‐Kadi Ayman O. S.
Published: July 2024

The human aryl hydrocarbon receptor (AhR), a ligand‐dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA‐approved drugs binding to the allosteric site between α2 of bHLH and PAS‐A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR‐ARNT‐DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS‐B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.
Simultaneous detection of three hypoxia‐inducible factor stabilizers—molidustat, roxadustat, and vadadustat—in multiple keratinized matrices and its application in a doping context
Authors: Checkouri Anne , Gheddar Laurie , Arbouche Nadia , Raul Jean‐Sébastien , Kintz Pascal
Published: July 2024

In a doping case, a top athlete challenged an anti‐doping rule violation, involving molidustat. Molidustat is a stabilizing agent of the hypoxia‐inducible factor (HIF) recently developed. It is currently undergoing clinical trials for anemia associated with chronic kidney disease. HIF stabilizers are banned at all times by the World Anti‐Doping Agency (class S2). Because of their pharmacological proprieties, these new drugs can enhance athletic performance. The athlete's defense wanted to analyze multiple keratinized matrices as they allow long‐term investigations. Requests concerning HIF stabilizers are constantly growing. We have therefore developed a liquid chromatography coupled with tandem mass spectrometry method to identify and quantify three molecules of this class: molidustat, vadadustat, and roxadustat. Thirty milligrams of keratinized matrices were incubated in 1 mL of pH 8.4 diammonium hydrogen phosphate buffer for 16 h at 40°C with 1 ng of testosterone‐D3, used as internal standard. After extraction with ethyl acetate/diethyl ether (80/20), the organic phase was evaporated, and the dry residue was reconstituted in 30 μL of initial phase. The method was linear from 5 to 1000 pg/mg for the three analytes. Limits of quantification were 2, 0.5, and 5 pg/mg for molidustat, roxadustat, and vadadustat, respectively. The analysis of the athlete's head hair (collected 1 month after the urine test) showed a concentration of molidustat of 135 pg/mg, and his beard hair and his fingernails clippings contained 55 and 40 pg/mg, respectively.
Occurrence and persistence of pseudo‐tail spots in the barn swallow
Authors: Hasegawa Masaru
Published: July 2024

While numerous studies have confirmed sexual selection for ornamental traits in animals, it remains unclear about how animals exaggerate ornamentation across traits. I found that some Asian barn swallows Hirundo rustica gutturalis possessed “pseudo‐tail spots” on their undertail coverts adjacent to a well‐known sexual signal, the white tail spots. A close inspection showed their remarkable resemblance, and, as a consequence, pseudo‐tail spots appear to add white spots to the uniformly black central tail feathers, increasing the total number and area of white spots when spread tails are viewed from below. Pseudo‐tail spots on the undertail covers do not incur any flight cost, unlike the white tail spots on the tail itself, and thus presence of pseudo‐tail spots can represent an initial stage of a deceptive elaboration as predicted by sexual selection theory (i.e., males can elaborate traits with no additional flight cost, uncoupling flight cost and trait expression). The frequency of pseudo‐tail spots in the study population remained low even a decade after the first observation (ca. 7%), but was higher compared to other populations (e.g., 1% in another Japanese population). The slow progress of evolution, perhaps due to the low detectability of the trait, provides a unique opportunity to observe contemporary evolution of ornament exaggeration across traits. Further research with wider spatial and temporal coverage is needed to better understand the evolutionary and ecological importance of the trait.
Interpretation of elevated baseline concentrations and serial changes of high‐sensitivity cardiac troponin T in confirmed muscular dystrophies
Authors: Yildirim Mustafa , Reich Christoph , Salbach Christian , Pribe‐Wolferts Regina , Milles Barbara Ruth , Täger Tobias , Mueller‐Hennessen Matthias , Weiler Markus , Meder Benjamin , Frey Norbert , Giannitsis Evangelos
Published: July 2024

Aims

Concentrations of high‐sensitivity cardiac troponin T (hs‐cTnT) are frequently elevated in stable patients with confirmed muscle dystrophies. However, sparse information is available on the interpretation of serial concentration changes.

Methods

Hs‐cTnT was collected in 35 stable outpatients with confirmed skeletal muscle dystrophies at 0 and 1 h and after 6–12 months during scheduled outpatient visits. We simulated the effectiveness of the European Society of Cardiology (ESC) 0/1 h algorithm and assessed biological variation at 6–12 months using two established methods: reference change value (RCV) and minimal important difference (MID).

Results

Median baseline hs‐cTnT concentrations were 34.4 ng/L [inter‐quartile range (IQR): 17.5–46.2], and values > 99th percentile upper limit of normal were present in 34 of 35 patients. All patients were stable without cardiovascular adverse events during a follow‐up of 6.6 months (IQR: 6–7). Median concentration change was 1.9 ng/L (IQR: 0.7–3.2) and 0.8 ng/L (IQR: 0–7.0) at 60 min and 6–9 months, respectively. Applying the criteria of the ESC 0/1 h algorithm for triage of suspected acute coronary syndrome (ACS) showed poor overall effectiveness of baseline hs‐cTnT values. No patient would qualify for rule‐out based on hs‐cTnT less than the limit of detection, whereas five cases would qualify for rule‐in based on hs‐cTnT ≥ 52 ng/L. Biological variabilities at 6–12 months per MID and RCV were 1.2 ng/L [95% confidence interval (CI): 0.7–2.1] and 28.6% (95% CI: 27.9–29.6), respectively. A total of 8 (22.9%) and 25 (71.4%) cases exceeded the biological variation range, suggesting some additional myocardial damage.

Conclusions

The high prevalence of elevated hs‐cTnT could negatively impact the effectiveness of rule‐out and rule‐in strategies based on a single hs‐cTnT value. Knowledge of the physiological and biological variation of hs‐cTnT after 6–12 months is helpful to detect the progression of cardiac involvement or to search for cardiac complications including but not limited to arrhythmias that may trigger acute or chronic myocardial damage.
Treatment time limit for successful weaning from veno‐arterial extracorporeal membrane oxygenation in cardiogenic shock
Authors: Suzuki Sho , Ito Kii , Teraoka Nami , Okuma Yukari , Kimura Kazuhiro , Minamisawa Masatoshi , Ebisawa Soichiro , Motoki Hirohiko , Imamura Hiroshi , Seto Tatsuichiro , Kuwahara Koichiro
Published: July 2024

Aims

Knowing the upper time limit for successful weaning from temporary mechanical circulatory support in cardiogenic shock will help with decision‐making regarding advanced heart failure (HF) therapy or considering withdrawal of care. The aim of this study was to investigate the association between the support duration and successful weaning from veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) in patients with cardiogenic shock.

Methods and results

A retrospective single‐centre cohort study was conducted between January 2013 and June 2023. It included 100 consecutive patients with cardiogenic shock who were treated with VA‐ECMO. Patients with out‐of‐hospital cardiac arrest were excluded. The primary outcome was successful weaning from VA‐ECMO (i.e., VA‐ECMO decannulation and survival to discharge). The association between the length of support duration and the weaning success rate was analysed. Patients were divided into three groups according to ECMO support duration: Group A (≤7 days), Group B (8–14 days), and Group C (≥15 days). Multivariable logistic regression analysis was used to evaluate the impact of the length of support duration on successful weaning of VA‐ECMO. The median age was 67 years, and 73% of study participants were male. The underlying aetiologies of cardiogenic shock were as follows: acute myocardial infarction, 50; fulminant myocarditis, 19; cardiomyopathy, 15; valvular heart disease, 8; and other, 8. Seventy‐five patients (75%) were attempted to wean VA‐ECMO, and 67 moved on to decannulation. In total, 43 (43%) patients were successfully weaned from VA‐ECMO. The median length of ECMO support duration was 8 [3–15] days. Compared with those who underwent successful ECMO decannulation, those who did not had a significantly longer support duration of VA‐ECMO (5 [3–9] days vs. 12 [3–22] days, P = 0.004). The weaning success rate was significantly higher in patients with short support duration; 58% (29/50), 40% (10/25), 16% (4/25) in Groups A, B, and C, respectively (P = 0.002). Overall, none of the patients supported for over 24 days (0/11) were successfully weaned from VA‐ECMO. On multivariable logistic regression analysis, the length of support duration was independently associated with successful weaning after adjusting for age, sex, underlying aetiology, and left ventricular ejection fraction (odds ratio, 0.813 [per 3 days]; 95% confidence interval, 0.679–0.914; P = 0.025).

Conclusions

Long support duration of VA‐ECMO was significantly associated with a low rate of successful weaning in patients with cardiogenic shock. Patients who require VA‐ECMO for over 1 week should start considering advanced HF therapy or withdrawal of care.
Association of COPD with adverse outcomes in heart failure patients with preserved ejection fraction
Authors: Xu Shuo , Gu Zhenbang , Zhu Wengen , Feng Shenghui
Published: July 2024

We performed a systematic review and meta‐analysis to detect the impact of chronic obstructive pulmonary disease (COPD) on the prognosis of heart failure patients with preserved ejection fraction (HFpEF). We systematically screened eligible literature from three electronic databases, PubMed, EMBASE and Cochrane Library, up to April 2023. Two researchers participated in data collection independently. Risk ratios (RRs) from included studies with 95% confidence intervals (CIs) were pooled in the Review Manager version 5.40 software using a random‐effects model for analysis. A total of 11 studies (3 post hoc analyses of RCTs and 8 observational studies) with 18 602 participants were included in this meta‐analysis. After pooling all the data from eligible studies, our results indicated that COPD was associated with an increased risk of hospitalization (RR = 1.66, 95% CI, 1.47–1.87, P < 0.00001), mortality (RR = 1.62, 95% CI, 1.34–1.95, P < 0.00001), and the composition of hospitalization or mortality (RR = 1.84, 95% CI, 1.35–2.51, P < 0.001) in patients with HFpEF. In a subgroup analysis, the risks of cardiovascular‐related mortality (RR = 1.59, 95% CI, 1.30–1.93, P < 0.00001) and post‐discharge mortality risk (RR = 2.57, 1.34–4.93, P < 0.01) were increased in HFpEF patients comorbid with COPD, and these associations were also detected in HF‐caused hospitalization (RR = 1.64, 95% CI, 1.44–1.87, P < 0.00001). Evidence from existing studies supported that COPD was an independent prognostic risk factor for patients with HFpEF. Developing rapid clinical diagnostic indicators and early use of novel drugs such as SGLT‐2 and ARNI may improve the prognosis of this population, deserving further study.
Design of rechargeable/regenerative future AA liquid green battery for low power applications
Authors: Singh Ajay Kumar , Joshi Jetendra , Kumar Praveen , Gangwar Sumeet
Published: July 2024

Generation of green energy is critical for addressing the environmental pollution and saving aquatic life in future by reducing the greenhouse gas. Green energy is generated using sources like wind, water, sun, living plants, and so on. These sources are essential for long‐term efforts to mitigate climate change. The large‐scale use of green energies will contribute to sustainable development which ensure access to reliable, and chemical free energy to power up the portable devices. This research article proposes design of green rechargeable and regenerative battery for brighter future. The proposed battery is not only rechargeable and eco‐friendly but also non‐flammable and can survive at extreme weather conditions T = 70°C (V = 1.52 V, I = 75.5 μA) and T = −65°C (V = 1.52 V, I = 55.2 μA). The electric current of the designed battery also depends on shaking/rotation. The proposed battery can charge 80% to 90% of its initial value within 30 to 40 minutes which makes it a favorable candidate where faster recharging is needed. The designed battery does not show any heating effect even at T = 70°C. Since, battery is free from any chemical, it is therefore does not release any hazardous chemicals once dispose of.
Analysis of volatile floral fragrance components of Camellia yuhsienensis Hu by HS‐SPME/GC–MS
Authors: Yuan Yaqi , Tan XinJian , Zhong Qiuping , Ge Xiaoning , Yan Chao , Guo Hongyan , Zou Yuling , Cao Linqing , Wang Jinfeng , Zhou Youcheng , Yuan YongJiao
Published: July 2024

The flowers of selected Camellia yuhsienensis Hu specimens were studied at different stages of flowering to determine the volatile components of floral fragrance and how their concentrations changed during efflorescence. The mechanism of fragrance formation and release was also studied in order to provide a theoretical basis for the practical use of C. yuhsienensis Hu flowers. Headspace solid‐phase microextraction (HS‐SPME) was used to extract the natural floral volatile oils of C. yuhsienensis Hu at the different stages, and the floral fragrance components were analysed by gas chromatography–mass spectrometry (GC–MS). A total of 31, 59 and 55 compounds were detected at the budding, early‐blooming and full‐blooming stages respectively. These floral fragrance components included terpene alcohols, as well as other aromatic and aliphatic compounds, and the relative concentrations of the various compounds at different stages of flowering, were different, and those of fatty alcohols and terpene alcohols having higher relative contents at all stages. The main component at the budding stage of C. yuhsienensis Hu was ocimene, which has a grassy fragrance, accompanied by the scent of neroli oil, which gives it a refreshing, gentle and sweet, and explains why the floral fragrance of C. yuhsienensis Hu at the budding stage is extremely thin: the main component during the early‐blooming stage was 3‐carene. A higher percentage of 3‐carene increased the sweetness of the scent, manifesting the typical fragrant characteristics of C. yuhsienensis Hu. The main identified compound at the full‐blooming stage was α‐farnesene, which has a delicate fragrance, accompanied by a balsamic aroma, similar to the scent of gardenia, which is consistent with the sensory characteristics of C. yuhsienensis Hu.
MRI‐based axis‐referenced morphometric model corresponding to lamellar organization for assessing hippocampal atrophy in dementia
Authors: Gao Na , Ye Chenfei , Chen Hantao , Hao Xingyu , Ma Ting
Published: July 2024

Research on the local hippocampal atrophy for early detection of dementia has gained considerable attention. However, accurately quantifying subtle atrophy remains challenging in existing morphological methods due to the lack of consistent biological correspondence with the complex curving regions like the hippocampal head. Thereby, this article presents an innovative axis‐referenced morphometric model (ARMM) that follows the anatomical lamellar organization of the hippocampus, which capture its precise and consistent longitudinal curving trajectory. Specifically, we establish an “axis‐referenced coordinate system” based on a 7 T ex vivo hippocampal atlas following its entire curving longitudinal axis and orthogonal distributed lamellae. We then align individual hippocampi by deforming this template coordinate system to target spaces using boundary‐guided diffeomorphic transformation, while ensuring that the lamellar vectors adhere to the constraint of medial‐axis geometry. Finally, we measure local thickness and curvatures based on the coordinate system and boundary surface reconstructed from vector tips. The morphometric accuracy is evaluated by comparing reconstructed surfaces with those directly extracted from 7 T and 3 T MRI hippocampi. The results demonstrate that ARMM achieves the best performance, particularly in the curving head, surpassing the state‐of‐the‐art morphological models. Additionally, morphological measurements from ARMM exhibit higher discriminatory power in distinguishing early Alzheimer's disease from mild cognitive impairment compared to volume‐based measurements. Overall, the ARMM offers a precise morphometric assessment of hippocampal morphology on MR images, and sheds light on discovering potential image markers for neurodegeneration associated with hippocampal impairment.
EEG/MEG source imaging of deep brain activity within the maximum entropy on the mean framework: Simulations and validation in epilepsy
Authors: Afnan Jawata , Cai Zhengchen , Lina Jean‐Marc , Abdallah Chifaou , Delaire Edouard , Avigdor Tamir , Ros Victoria , Hedrich Tanguy , von Ellenrieder Nicolas , Kobayashi Eliane , Frauscher Birgit , Gotman Jean , Grova Christophe
Published: July 2024

Electro/Magneto‐EncephaloGraphy (EEG/MEG) source imaging (EMSI) of epileptic activity from deep generators is often challenging due to the higher sensitivity of EEG/MEG to superficial regions and to the spatial configuration of subcortical structures. We previously demonstrated the ability of the coherent Maximum Entropy on the Mean (cMEM) method to accurately localize the superficial cortical generators and their spatial extent. Here, we propose a depth‐weighted adaptation of cMEM to localize deep generators more accurately. These methods were evaluated using realistic MEG/high‐density EEG (HD‐EEG) simulations of epileptic activity and actual MEG/HD‐EEG recordings from patients with focal epilepsy. We incorporated depth‐weighting within the MEM framework to compensate for its preference for superficial generators. We also included a mesh of both hippocampi, as an additional deep structure in the source model. We generated 5400 realistic simulations of interictal epileptic discharges for MEG and HD‐EEG involving a wide range of spatial extents and signal‐to‐noise ratio (SNR) levels, before investigating EMSI on clinical HD‐EEG in 16 patients and MEG in 14 patients. Clinical interictal epileptic discharges were marked by visual inspection. We applied three EMSI methods: cMEM, depth‐weighted cMEM and depth‐weighted minimum norm estimate (MNE). The ground truth was defined as the true simulated generator or as a drawn region based on clinical information available for patients. For deep sources, depth‐weighted cMEM improved the localization when compared to cMEM and depth‐weighted MNE, whereas depth‐weighted cMEM did not deteriorate localization accuracy for superficial regions. For patients' data, we observed improvement in localization for deep sources, especially for the patients with mesial temporal epilepsy, for which cMEM failed to reconstruct the initial generator in the hippocampus. Depth weighting was more crucial for MEG (gradiometers) than for HD‐EEG. Similar findings were found when considering depth weighting for the wavelet extension of MEM. In conclusion, depth‐weighted cMEM improved the localization of deep sources without or with minimal deterioration of the localization of the superficial sources. This was demonstrated using extensive simulations with MEG and HD‐EEG and clinical MEG and HD‐EEG for epilepsy patients.
Awareness of embodiment enhances enjoyment and engages sensorimotor cortices
Authors: Moffat Ryssa , Cross Emily S.
Published: July 2024

Whether in performing arts, sporting, or everyday contexts, when we watch others move, we tend to enjoy bodies moving in synchrony. Our enjoyment of body movements is further enhanced by our own prior experience with performing those movements, or our ‘embodied experience’. The relationships between movement synchrony and enjoyment, as well as embodied experience and movement enjoyment, are well known. The interaction between enjoyment of movements, synchrony, and embodiment is less well understood, and may be central for developing new approaches for enriching social interaction. To examine the interplay between movement enjoyment, synchrony, and embodiment, we asked participants to copy another person's movements as accurately as possible, thereby gaining embodied experience of movement sequences. Participants then viewed other dyads performing the same or different sequences synchronously, and we assessed participants' recognition of having performed these sequences, as well as their enjoyment of each movement sequence. We used functional near‐infrared spectroscopy to measure cortical activation over frontotemporal sensorimotor regions while participants performed and viewed movements. We found that enjoyment was greatest when participants had mirrored the sequence and recognised it, suggesting that awareness of embodiment may be central to enjoyment of synchronous movements. Exploratory analyses of relationships between cortical activation and enjoyment and recognition implicated the sensorimotor cortices, which subserve action observation and aesthetic processing. These findings hold implications for clinical research and therapies seeking to foster successful social interaction.
Cultural blind spots: Identifying hidden psychosocial hazards in the workplace
Authors: Kiaos Theaanna
Published: July 2024

Issue Addressed

This article presents a framework to identify hidden psychosocial hazards and emerging mental health risks in the workplace, thereby assisting Persons Conducting a Business or Undertaking. The framework adds value to the processes outlined in SafeWork NSW's Code of Practice for Managing Psychosocial Hazards At Work. Specifically, the article documents a framework to analyse microcultures and back stage sites of enactment where psychosocial hazards and risks may be hidden or obscured in workplace settings.

Background

The article's framework aims to bring to the surface both the intra and interpersonal tensions employees experience in the social reality they inhabit while they perform their work, thereby positively contributing to organisations and PCBUs by helping them create healthy workplace cultures and psychological safety.

Methods

Specifically, the article discusses partnering with an organisational ethnographer when a PCBU embarks upon psychosocial investigations to: gain access, select employee participants, start conversations, establish rapport, build trust, collect and analyse data.

Conclusion

This article theoretically contributes to health promotion literatures by offering organisations a complementary way of extracting deeper insights and understandings of psychosocial hazards and emerging mental health risks which are not apparent with traditional methods of inquiry.
Bi‐directional and multi‐modal effects of dexamphetamine on spatial binding windows in healthy individuals
Authors: Lim Mark J. H. , Loffman Sean J. , Gaus Katharina , Slawik Sophie V. , Iyyalol Rajan , Lee Joseph W. Y. , Hepple Emily K. , Martin‐Iverson Mathew T.
Published: July 2024

Objectives

Stimuli that are separated by a short window of space or time, known as spatial and temporal binding windows (SBW/TBWs), may be perceived as separate. Widened TBWs are evidenced in schizophrenia, although it is unclear if the SBW is similarly affected. The current study aimed to assess if dexamphetamine (DEX) may increase SBWs in a multimodal visuo‐tactile illusion, potentially validating usefulness as an experimental model for multimodal visuo‐tactile hallucinations in schizophrenia, and to examine a possible association between altered binding windows (BWs) and working memory (WM) suggested by previous research.

Methods

A placebo‐controlled, double‐blinded, and counter‐balanced crossover design was employed. Permuted block randomisation was used for drug order. Healthy participants received DEX (0.45 mg/kg, PO, b.i.d.) or placebo (glucose powder) in capsules. The Rubber Hand Illusion (RHI) and Wechsler Adult Intelligence Scale Spatial Span was employed to determine whether DEX would alter SBWs and WM, respectively. Schizotypy was assessed with a variety of psychological scales.

Results

Most participants did not experience the RHI even under normal circumstances. Bi‐directional and multimodal effects of DEX on individual SBWs and schizotypy were observed, but not on WM.

Conclusions

Bidirectional multimodal effects of DEX on the RHI and SBWs were observed in individuals, although not associated with alterations in WM.
A proteome‐wide analysis unveils a core Epstein–Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations
Authors: Sarathkumara Yomani D. , Xian Rena R. , Liu Zhiwei , Yu Kelly J. , Chan John K. C. , Kwong Yok‐Lam , Lam Tai Hing , Liang Raymond , Chiu Brian , Xu Jun , Hu Wei , Ji Bu‐Tian , Coghill Anna E. , Kelly Ashton M. , Pfeiffer Ruth M. , Rothman Nathaniel , Ambinder Richard F. , Hildesheim Allan , Lan Qing , Proietti Carla , Doolan Denise L.
Published: July 2024

Epstein–Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East‐Asian hospital‐based case–control study. We identified 16 IgG antibodies significantly elevated in EBV‐positive cHL compared with controls, defining an “East‐Asian antibody signature of EBV‐positive cHL.” We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case–control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the “East‐Asian antibody signature of EBV‐positive cHL” exhibited significant associations with cHL in the European population. Conversely, we assessed the “European antibody signature of EBV‐positive cHL” identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East‐Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East‐Asian population. This cross‐comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti‐EBV IgG antibodies (LMP‐1, TK, BALF2, BDLF3, and BBLF1), found in both population‐specific antibody signatures, represent a “core signature of EBV‐positive cHL.” Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV‐positive cHL independent of population‐specific factors.
Three biomarkers (HER2, PD‐L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience
Authors: Sewastjanow‐Silva Matheus , Kwiatkowski Evan , Yamashita Kohei , Abdelhakeem Ahmed , Yoshimura Katsuhiro , Vicentini Ernesto R. , Pizzi Melissa P. , Jin Jiankang , Fan Yibo , Zou Gengyi , Wang Lingzhi , Yin Feng , Dhar Shilpa S. , Blum Murphy Mariela , Mares Jeannette E. , Li Jenny J. , Gan Qiong , Waters Rebecca E. , Rogers Jane E. , Ajani Jaffer A.
Published: July 2024

Human epidermal growth factor receptor‐2 (HER2), programmed death‐ligand 1 (PD‐L1), and microsatellite (MS) status are well‐established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD‐L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.
Association between risk of infant death and birth‐weight z scores according to gestational age: A nationwide study using the Finnish Medical Birth Register
Authors: Hocquette Alice , Pulakka Anna , Metsälä Johanna , Heikkilä Katriina , Zeitlin Jennifer , Kajantie Eero
Published: July 2024

Objective

To investigate the association between infant mortality and birth weight using estimated fetal weight (EFW) versus birth‐weight charts, by gestational age (GA).

Methods

This nationwide population‐based study used data from the Finnish Medical Birth Register from 2006 to 2016 on non‐malformed singleton live births at 24–41+6 weeks of gestation (N = 563 630). The outcome was death in the first year of life. Mortality risks by birth‐weight z score, defined as a continuous variable using Maršál's EFW and Sankilampi's birth‐weight charts, were assessed using generalized additive models by GA (24–27+6, 28–31+6, 32–36+6, 37–38+6, 39–41+6 weeks). We calculated z score thresholds associated with a two‐ and three‐fold increased risk of infant death compared with newborns with a birth weight between 0 and 0.675 standard deviations.

Results

The z score thresholds (with corresponding centiles in parentheses) associated with a two‐fold increase in infant mortality were: −3.43 (<0.1) at 24–27+6 weeks, −3.46 (<0.1) at 28–31+6 weeks, −1.29 (9.9) at 32–36+6 weeks, −1.18 (11.9) at 37–38+6 weeks, and − 1.34 (9.0) at 39–41+6 weeks according to the EFW chart. These values were − 2.43 (0.8), −2.62 (0.4), −1.34 (9.0), −1.37 (8.5), and − 1.43 (7.6) according to the birth‐weight chart.

Conclusion

The association between birth weight and infant mortality varies by GA whichever chart is used, suggesting that different thresholds for the screening of growth anomalies could be used across GA to identify high‐risk newborns.
Different endometrial preparation protocols on first frozen–thawed embryo transfer outcomes after hysteroscopic polypectomy: A retrospective cohort study
Authors: Ji Hui , Zhou Qiao , Zhang Song , Dong Li , Zhao Chun , Ling Xiu‐feng
Published: July 2024

Objective

To evaluate the optimal endometrial preparation protocol for frozen–thawed embryo transfer (FET) following hysteroscopic polypectomy.

Methods

This was a retrospective clinical cohort study involving 464 patients who underwent their first FET after polyp resection between January 2021 and July 2023. The cohorts were categorized into three groups: the natural cycle (NC) group (n = 139), the ovarian induction (OI) group (n = 117), and the hormone replacement therapy (HRT) group (n = 208).

Results

In the initial unadjusted analysis, both NC and OI cycles exhibited similar pregnancy rates but were associated with significantly higher implantation rate (56.5%, 57.1% vs 42.0%, P < 0.001), clinical pregnancy rate (73.4%, 74.4% vs 57.2%, P = 0.001), and ongoing pregnancy rate (OPR; 67.6%, 63.2% vs 51.0%, P = 0.005) compared to the HRT group. Additionally, the three groups demonstrated comparable abortion rate (7.8%, 14.9% vs 10.9%, P = 0.299). After adjusting for potential confounders in the multiple logistic regression model, the HRT protocol resulted in a 54% significantly lower OPR compared to the NC protocol (adjusted odds ratio [aOR] = 0.46, 95% confidence interval [CI]: 0.28–0.77; P = 0.003). Meanwhile, the OPR difference between the OI protocol and the NC protocol remained insignificant (OI vs NC: aOR = 0.62, 95% CI: 0.35–1.12; P = 0.112).

Conclusion

The ovulatory‐FET scheme (NC and OI) following hysteroscopic polyp resection displayed promising clinical outcomes compared with HRT‐FET scheme. The regimen without exogenous estrogen administration should be prioritized for endometrial preparation protocol after polypectomy.