bluuebunny/crossref_metadata_2025 huggingface dataset:
The Future of Iran's Nuclear Dossier: Possible Options
Authors: Chitsazian Mohammad Reza
Published: April 2022

For more than two decades, the nuclear issue has overshadowed Iran's foreign policy, becoming a major crisis in international politics. On the one hand, great powers and some regional countries are concerned about the military dimension of Iran's nuclear program; on the other hand, Iran is pursuing its nuclear rights confirmed by the International Atomic Energy Agency. The challenge has encountered ups and downs in recent years, from the nuclear deal in 2015 to the verge of war between Iran and the United States during Donald Trump's presidency. This background has obscured the future of nuclear Iran's dossier. Accordingly, this research aims to address possible scenarios facing the parties. Based on the current realities, it concludes that the best possible option is returning to the nuclear deal signed in 2015. If both sides fulfill their commitments, it will pave the way for resolving other disputes.
Functional characterization of the first lipoyl‐relay pathway from a parasitic protozoan
Authors: Scattolini Albertina , Lavatelli Antonela , Vacchina Paola , Lambruschi Daniel A. , Mansilla María C. , Uttaro Antonio D.
Published: April 2022

Lipoic acid (LA) is a sulfur‐containing cofactor covalently attached to key enzymes of central metabolism in prokaryotes and eukaryotes. LA can be acquired by scavenging, mediated by a lipoate ligase, or de novo synthesized by a pathway requiring an octanoyltransferase and a lipoate synthase. A more complex pathway, referred to as “lipoyl‐relay”, requires two additional proteins, GcvH, the glycine cleavage system H subunit, and an amidotransferase. This route was described so far in Bacillus subtilis and related Gram‐positive bacteria, Saccharomyces cerevisiae, Homo sapiens, and Caenorhabditis elegans. Using collections of S. cerevisiae and B. subtilis mutants, defective in LA metabolism, we gathered evidence that allows us to propose for the first time that lipoyl‐relay pathways are also present in parasitic protozoa. By a reverse genetic approach, we assigned octanoyltransferase and amidotransferase activity to the products of Tb927.11.9390 (TblipT) and Tb927.8.630 (TblipL) genes of Trypanosoma brucei, respectively. The B. subtilis model allowed us to identify the parasite amidotransferase as the target of lipoate analogs like 8‐bromo‐octanoic acid, explaining the complete loss of protein lipoylation and growth impairment caused by this compound in T. cruzi. This model could be instrumental for the screening of selective and more efficient chemotherapies against trypanosomiases.
Synthesis of 4‐methylvaleric acid, a precursor of pogostone, involves a 2‐isobutylmalate synthase related to 2‐isopropylmalate synthase of leucine biosynthesis
Authors: Wang Chu , Wang Ying , Chen Jing , Liu Lang , Yang Mingxia , Li Zhengguo , Wang Chengyuan , Pichersky Eran , Xu Haiyang
Published: April 2022

We show here that the side chain of pogostone, one of the major components of patchouli oil obtained fromPogostemon cablinand possessing a variety of pharmacological activities, is derived from 4‐methylvaleric acid.

We also show that 4‐methylvaleric acid is produced through the one‐carbon α‐ketoacid elongation pathway with the involvement of the key enzyme 2‐isobutylmalate synthase (IBMS), a newly identified enzyme related to isopropylmalate synthase (IPMS) of leucine (Leu) biosynthesis.

Site‐directed mutagenesis identified Met132in the N‐terminal catalytic region as affecting the substrate specificity of PcIBMS1. Even though PcIBMS1 possesses the C‐terminal domain that in IPMS serves to mediate Leu inhibition, it is insensitive to Leu.

The observation of the evolution of IBMS from IPMS, as well as previously reported examples of IPMS‐related genes involved in making glucosinolates in Brassicaceae, acylsugars in Solanaceae, and flavour compounds in apple, indicate that IPMS genes represent an important pool for the independent evolution of genes for specialised metabolism.
Evaluation of halitosis parameters in patients undergoing head and neck radiotherapy
Authors: Maluf Gustavo Valerio , Caldas Rogério Jardim , Fregnani Eduardo Rodrigues , Antunes Héliton Spindola , Tobias Matheus Augusto Siscotto , da Silva Santos Paulo Sérgio
Published: April 2022

Objectives

To assess halitosis parameters using OralChroma™ and the correlation with salivary flow, oral hygiene index, radiation dose, and tongue‐coating index among irradiated head and neck cancer patients compared to patients without cancer.

Materials and Methods

This cross‐sectional study enrolled irradiated and non‐irradiated patients divided into two groups. Hydrogen sulfide, methyl mercaptan, and dimethyl sulfide (DMS) levels were measured using a gas chromatograph, and sialometry was performed. The tongue‐coating index and simplified oral hygiene index were also assessed.

Results

Thirty‐eight patients were allocated to each group. Volatile sulfur compound levels were above the thresholds in both groups. Non‐irradiated individuals showed higher levels of hydrogen sulfide and dimethyl sulfide. Patients with asialia had an inexpressive tongue‐coating index and increased dimethyl sulfide levels. A decrease in salivary flow rate was followed by a significant increase in volatile sulfur compound levels. Higher doses of radiation to the submandibular salivary glands were associated with higher concentrations of sulfide and methyl mercaptan.

Conclusions

Head and neck radiotherapy may be important in the development of halitosis. Irradiated patients with asialia presented insignificant lingual biofilm. Consequently, lower levels of volatile sulfur compounds were detected in this group. Asialia, a severe radiation‐induced hyposalivation, impacted the levels of DMS (extraoral origin).
Arms Control Dialogue or Gray Zone Talks? Pitfalls of the Discourses of Denuclearization of the Korean Peninsula and Nuclear Arms Control*
Authors: Ban Kil Joo
Published: April 2022

What makes the schemes to address Pyongyang's nuclear program so ineffective? Aside from conventional explanations, two gray zone discourses are at play. First, the gray zone discourse of denuclearization of the Korean Peninsula has been viable since 1991. Second, another gray zone discourse of nuclear arms control with North Korea has been gathering pace recently. Gray zone discourses blur the line between North Korea and the United States regarding who should be a targeted state. How are gray zone discourses at play in the long process of negotiations and talks? Who is the most likely to win if these gray zone discourses remain intact? These blurred discourses also help North Korea become a recognized nuclear power and a normal state in an international arena. Leaving the distorted mechanism unchecked can encourage a gray zone perpetrator to seize the initiative of tackling nuclear issues, allowing North Korea to achieve a final goal of nuclearization. As part of the efforts to make gray zone discourses unfunctional, three strategic and policy remedies need to be at the forefront: making black‐and‐white discourses, increasing leverage to North Korea, and establishing a zero‐gray‐zone strategy.
The Reaction of Taiwan Civil Society Towards Cross‐Strait Integration During the Period from 2008 to 2016: Spillover or Politicization?
Authors: Lai Yun‐Chen
Published: April 2022

This study explores the integration attempt between Taiwan and China during the period from 2008 to 2016, focusing on the perspective of Taiwan civil society, as both the initiation and the deadlock of the cross‐strait integration during this period were primarily triggered by Taiwan. This research adopts functionalist theory, as the design of integration derived from neo‐functionalism and the deadlock of integration would be better explained by politicization, which constitutes the emphasis of post‐functionalism. The findings demonstrate that different extents of politicization made the fates of the two major integration attempts during that period (Economic Cooperation Framework Agreement and Cross‐Strait Service Trade Agreement) dissimilar. It is further concluded that common identity is the key factor for cross‐strait integration in the future.
Bolstering the Alliance for a Trilateralism‐Based Security Strategy for South Korea in Times of US–China Rivalry*
Authors: Nam Chang‐hee , Song Sang‐ho
Published: April 2022

As the strategic competition between the United States and China intensifies, South Korea is facing growing pressure to chart an optimal diplomatic strategy to navigate the convoluted geopolitics and foster lasting peace on the Korean Peninsula and beyond. At this crucial juncture, this study examines multi‐faceted, capacity‐building measures for peace aimed at precluding Sino–US friction in the East and South China Seas from spilling over into the Korean Peninsula. This article presents a road map to stimulate and reinvigorate security cooperation among South Korea, the United States, and Japan and economic cooperation among South Korea, China, and Japan in a virtuous cycle, and by extension to craft a dialogue channel among South Korea, the United States, and China. It also puts forward a three‐stage program for the evolution of the South Korea–US alliance whereby South Korea secures flexibility in its approach to China based on the robust trust of the alliance. This is to enable South Korea to assume a key role in connecting the three trilateral cooperation channels with the development of the Seoul–Washington alliance being a key driver to expand Seoul's diplomatic capacity. In the end, this study envisions a foreign policy model for South Korea that would allow the middle‐power country to punch above its weight by expanding the framework of cooperative security. It aims to ultimately pursue a multilateral, common security architecture in Northeast Asia, including China, which will serve as a multilayered catalyst to promote lasting peace on the Korean Peninsula.
Small paraquat resistance proteins modulate paraquat and ABA responses and confer drought tolerance to overexpressing Arabidopsis plants
Authors: Faragó Dóra , Zsigmond Laura , Benyó Dániel , Alcazar Rubén , Rigó Gábor , Ayaydin Ferhan , Rabilu Sahilu Ahmad , Hunyadi‐Gulyás Éva , Szabados László
Published: April 2022

Adaptation of higher plants to extreme environmental conditions is under complex regulation. Several small peptides have recently been described to modulate responses to stress conditions. The Small Paraquat resistance protein (SPQ) ofLepidium crassifoliumhas previously been identified due to its capacity to confer paraquat resistance to overexpressing transgenic Arabidopsis plants. Here, we show that overexpression of the closely related Arabidopsis SPQ can also enhance resistance to paraquat, while the Arabidopsisspq1mutant is slightly hypersensitive to this herbicide. Besides being implicated in paraquat response, overexpression of SPQs enhanced sensitivity to abscisic acid (ABA), and the knockoutspq1mutant was less sensitive to ABA. Both Lepidium‐ and Arabidopsis‐derived SPQs could improve drought tolerance by reducing water loss, stabilizing photosynthetic electron transport and enhancing plant viability and survival in a water‐limited environment. Enhanced drought tolerance ofSPQ‐overexpressing plants could be confirmed by characterizing various parameters of growth, morphology and photosynthesis using an automatic plant phenotyping platform with RGB and chlorophyll fluorescence imaging. Our results suggest that SPQs can be regulatory small proteins connecting ROS and ABA regulation and through that influence responses to certain stresses.
Utility of perinatal natriuretic peptide for predicting neonatal heart failure
Authors: Miyoshi Takekazu , Hosoda Hiroshi , Miyake Akira , Sakaguchi Heima , Kitano Masataka , Kurosaki Ken‐ichi , Shiraishi Isao , Nakai Michikazu , Nishimura Kunihiro , Miyazato Mikiya , Kangawa Kenji , Yoshimatsu Jun , Minamino Naoto
Published: April 2022

Background

We evaluated the significance of perinatal plasma natriuretic peptide (NP) levels in neonates with congenital heart defects (CHDs) or arrhythmias and determined whether measurement of perinatal plasma NP levels and echocardiographic assessment in utero could predict heart failure after birth.

Methods

The study was conducted between 2012 and 2016 to evaluate the correlation of perinatal atrial NP (ANP) and brain NP (BNP) levels at birth with the modified Ross score after birth and the cardiovascular profile (CVP) score before birth.

Results

A total of 122 singletons with CHDs or arrhythmias and 27 controls were analyzed. Neonatal blood sampling was performed at a median of 0.7 h (range, 0.1–1.5) after birth. The neonatal plasma ANP and BNP levels shortly after birth were significantly higher than those in the umbilical artery (UA) plasma. The ANP and BNP levels in UA and neonatal blood were correlated with the modified Ross score. The neonatal plasma ANP and BNP levels and the modified Ross scores were inversely correlated with the CVP score in neonates with CHDs or arrhythmias. The area under the receiver operating characteristic curve of UA ANP levels for predicting neonatal heart failure was highest among those for the CVP score, perinatal plasma ANP and BNP levels, and their combinations.

Conclusions

The plasma ANP and BNP levels increased markedly shortly after birth. Assessment of the UA plasma ANP level at birth and the CVP score in utero may be utilized to predict neonatal heart failure.
Neural correlates of temporal integration and segregation in metacontrast masking: A phenomenological study
Authors: Kraut Alexander T. A. , Albrecht Thorsten
Published: April 2022

Temporal integration and segregation have been investigated both in the research on the temporal mechanisms in visual perception and in the research on visual masking. Although both research lines share theoretical, methodological, and empirical similarities, there is little overlap between them and their models of temporal processing are incompatible. As a first step toward the unification of both lines of research, we investigated the electrophysiological correlates of temporal integration and segregation in a metacontrast masking paradigm. Participants reported in each trial whether they perceived the target‐mask sequence as a simultaneous or temporally segregated percept while their EEG was recorded. A comparison of both temporal report categories resulted in an ERP difference after stimulus presentation (200–450 ms) that closely resembles the contour integration negativity. Moreover, we found that phase states were shifted between perceptual report categories in the alpha (450–250 ms) and beta (225–125 ms) frequency band before stimulus presentation and induced a sinusoidal periodicity in later temporal report proportions. Thus, we show that neural correlates of temporal integration and segregation can be generalized to metacontrast masking. These findings emphasize the potential role of temporal mechanisms in the emergence of the masking phenomenon. Additionally, our findings validate our phenomenological approach by demonstrating similar neural correlates of temporal integration and segregation as in performance‐based tasks. Future research may profit from our phenomenological approach to disentangle the (neural) interplay between temporal and masking mechanisms.
Soil DNA chronosequence analysis shows bacterial community re‐assembly following post‐mining forest rehabilitation
Authors: Peddle Shawn D. , Bissett Andrew , Borrett Ryan J. , Bullock Paul , Gardner Michael G. , Liddicoat Craig , Tibbett Mark , Breed Martin F. , Krauss Siegfried L.
Published: April 2022

Mining activities modify both aboveground and belowground ecological communities, presenting substantial challenges for restoration. The soil microbiome is one of these impacted communities and performs important ecosystem functions but receives limited focus in restoration. Sequencing soil DNA enables accurate and cost‐effective assessment of soil microbiota, allowing for comparisons across land use, environmental, and temporal gradients. We used amplicon sequencing of the bacterial 16s rRNA gene extracted from soil samples across a 28‐year post‐mining rehabilitation chronosequence to assess soil bacterial composition and diversity following rehabilitation at a bauxite mine in Western Australia's jarrah forest. We show that while bacterial alpha diversity did not differ between reference and rehabilitated sites, bacterial community composition changed dramatically across the chronosequence, suggesting strong impacts by mining and rehabilitation activities. Bacterial communities generally became increasingly similar to unmined reference sites with time since rehabilitation. Soil from sites rehabilitated as recently as 14 years ago did not have significantly different communities to reference sites. Overall, our study provides evidence indicating the recovery of soil bacterial communities toward reference states following rehabilitation. Including several ecological reference sites revealed substantial natural variability in bacterial communities from within a single mine site. We urge future restoration chronosequence studies to sample reference sites that geographically span the restored sites and/or are spatially paired with restored sites to ensure this variability is captured and to improve any inferences on recovery.
Reliability Analysis of Artificial Intelligence Systems Using Recurrent Events Data from Autonomous Vehicles
Authors: Min Jie , Hong Yili , King Caleb B. , Meeker William Q.
Published: April 2022

Artificial intelligence (AI) systems have become increasingly common and the trend will continue. Examples of AI systems include autonomous vehicles (AV), computer vision, natural language processing and AI medical experts. To allow for safe and effective deployment of AI systems, the reliability of such systems needs to be assessed. Traditionally, reliability assessment is based on reliability test data and the subsequent statistical modelling and analysis. The availability of reliability data for AI systems, however, is limited because such data are typically sensitive and proprietary. The California Department of Motor Vehicles (DMV) oversees and regulates an AV testing program, in which many AV manufacturers are conducting AV road tests. Manufacturers participating in the program are required to report recurrent disengagement events to California DMV. This information is being made available to the public. In this paper, we use recurrent disengagement events as a representation of the reliability of the AI system in AV, and propose a statistical framework for modelling and analysing the recurrent events data from AV driving tests. We use traditional parametric models in software reliability and propose a new non-parametric model based on monotonic splines to describe the event process and to estimate the cumulative baseline intensity function of the event process. We develop inference procedures for selecting the best models, quantifying uncertainty and testing heterogeneity in the event process. We then analyse the recurrent events data from four AV manufacturers, and make inferences on the reliability of the AI systems in AV. We also describe how the proposed analysis can be applied to assess the reliability of other AI systems. This paper has online supplementary materials.
Chrysin enhances antitumour immunity response through the IL‐12‐STAT4 signal pathway in the B16F10 melanoma mouse model
Authors: Lu Ran , Wang Shuang , Jiang Shasha , Li Chenglin , Wang Yashuo , Li Ling , Wang Yunyang , Ma Guixin , Qiao Hongye , Leng Zhe , Niu Junyun , Tian Zibin , Wang Bin
Published: April 2022

Chrysin (CHR) is a flavonoid with extensive pharmacological activity. The molecular formula of CHR is C15H10O4. CHR is reported to have antioxidative, antitumour and antiviral functions. To evaluate its potential function as a vaccine adjuvant, we prepared a melanoma vaccine using a soluble protein extract of B16F10 melanoma cells as antigen and CHR as an adjuvant. The melanoma model was developed after two immunizations, and it was discovered that combining B16F10 soluble protein antigen‐mixed CHR vaccine could inhibit tumour growth in the mouse model, and the overall survival rate was higher than that of the B16F10 antigen vaccine alone. In vivo and in vitro experiments were conducted to determine whether CHR functioned as an adjuvant by activating antigen‐presenting cells (APCs). We discovered that CHR activated APCs both in vivo and in vitro and may enhance Th1 cell function by activating the IL12‐STAT4 signal pathway, thereby enhancing the antitumour response of cytotoxic T lymphocytes (CTLs) in vivo. Next, to verify the critical role of CD8+ T cells in suppressing melanoma development, we transplanted CD8+ T cells from immunized mice to B16F10 tumour‐bearing mice and discovered that the survival rate of tumour‐bearing mice was significantly prolonged. In summary, our experimental results indicate that CHR can be used as a potential adjuvant to enhance antigen immunogenicity, inhibit B16F10 tumour growth in mice and improve tumour immune response.
Successful ABO‐incompatible living donor kidney transplantation in a recipient who developed flow cytometry crossmatch‐positive donor‐specific class I HLA antibodies following COVID‐19 vaccination
Authors: Kim Jae Kwon , Bae Hyunjoo , Ko Geon Young , Lee Jihyun , Jung Jin , Jekarl Dong Wook , Choi Ae‐Ran , Lee Sangyoon , Chung Byung Ha , Yang Chul Woo , Park Sun Cheol , Oh Eun‐Jee
Published: April 2022

The effects of COVID‐19 vaccination on alloimmunization and clinical impact in transplant candidates remain largely unknown. In a 61‐year‐old man who had no donor‐specific antibodies (DSA) and was planned to undergo ABO‐incompatible kidney transplantation (ABOi KT), DSAs (anti‐A24, anti‐B51, and anti‐Cw14) developed after COVID‐19 vaccination. After desensitization therapy, antibody level was further increased, leading to flow cytometric crossmatch‐positive status. Donor‐specific T cell immunity using interferon‐gamma ELISPOT was continuously negative, whereas SARS‐CoV‐2 specific T cell immunity was intact. After confirming the C1q‐negative status of DSA, the patient received ABOi KT. The patient had stable graft function and suppressed alloimmunity up to 2 months after KT. COVID‐19 vaccination might relate to alloimmunization in transplant candidates, and desensitization through immune monitoring can help guide transplantation.
Exit Planning: What Steps Should a Seller Take to Maximize Sale Value When Selling a Business?
Authors: Orgeldinger J.
Published: April 2022

When elder entrepreneurs establish their businesses, they will be able to put their previous knowledge to good use in new and exciting ways. Because many business founders will sell their enterprises when they retire, the aging population and the concomitant increase in the number of older entrepreneurs will result in increased M&A activity. This article gives a quick review of the most crucial measures that anyone can take to position themselves for future sales success. The article focuses on the situation in Europe.  Prospective sellers should concentrate on a few essential processes, according to the author, to have important points to negotiate the sale and command the greatest selling price.
El ecumenismo de la caridad como aporte a la unidad de la familia humana (EG 245). Algunos criterios inspiradores de Francisco
Authors: Mauti Ricardo Miguel
Published: April 2022

La dimensión ecuménica ad intra y ad extra ha sido uno de los objetivos principales del Concilio Vaticano II y es también hoy una de las características más acentuadas del ministerio petrino, llamado a una conversión que posibilite el servicio a la unidad. Este servicio a la unidad de la Iglesia y de todo el género humano constituyen un signo de credibilidad del obispo de Roma, como pastor de la Iglesia que preside en la caridad.La elección de Francisco ha significado una renovación en el empeño ecuménico de toda la Iglesia, a la vez que una apertura de sus objetivos e interlocutores. Su estilo ecuménico fue desarrollándose a lo largo de su vida, particularmente durante los años de ministerio pastoral como arzobispo de Buenos Aires. El contacto con líderes de diferentes confesiones cristianas y de otras religiones, tanto a nivel de espiritualidad ecuménica e interreligiosa, como de diálogo social, fueron gestando un ethos propio, que lo distingue de sus predecesores.Nuestra contribución hace un primer acercamiento al contexto histórico (hechos y figuras) del movimiento ecuménico moderno, con las progresivas tomas de posiciones de la Iglesia Católica.En un segundo momento indago sobre las raíces vitales del estilo ecuménico de Bergoglio Francisco, con especial acento durante estos siete años de pontificado, signados por múltiples encuentros, celebraciones y declaraciones conjuntas.Luego propongo, en un intento de breve sistematización, algunos criterios orientadores para la pastoral ecuménica, basados en los principios de Evangelii gaudium sobre el diálogo social y la construcción de la paz.Culmino con algunas reflexiones abiertas sobre interrogantes que pueden plantearse a la recepción impostergable del ecumenismo y del diálogo interreligioso, en orden a un renovado servicio a la paz mundial.
Mechanics Informed Neutron Noise Monitoring to Perform Remote Condition Assessment for Reactor Vessel Internals
Authors: Banyay Gregory A. , Palamara Matthew J. , Preston Jessica N. , Smith Stephen D.
Published: April 2022

The use of neutron noise analysis in pressurized water reactors to detect and diagnose degradation represents the practice of pro-active structural health monitoring for reactor vessel internals. Recent enhancements to this remote condition monitoring and diagnostic computational framework quantify the sensitivity of the structural dynamics to different degradation scenarios. This methodology leverages benchmarked computational structural mechanics models and machine learning methods to enhance the interpretability of neutron noise measurement results. The novelty of the methodology lies not in the particular technologies and algorithms but our amalgamation into a holistic computational framework for structural health monitoring. Recent experience revealed the successful deployment of this methodology to pro-actively diagnose different degradation scenarios, thus enabling prognostic asset management for reactor structures.
A Cluster Based Algorithm Coupled With Shooting Method for Estimation of Parametric Clusters Yielding Optimal Stable Periodic Solutions in Nonlinear Vibrating Systems
Authors: Premchand V. P. , Balaram Bipin , Narayanan M. D. , Sajith A. S.
Published: April 2022

This work presents a novel cluster based optimization procedure for estimating parameter values that yield stable, periodic responses with desired amplitude in nonlinear vibrating systems. The parameter values obtained by conventional nonlinear optimization schemes, with minimization of amplitude as the objective, may not furnish periodic and stable responses. Moreover, global optimization strategies may converge to isolated optima that are sensitive to parametric perturbations. In practical engineering systems, unstable or isolated optimal orbits are not practically realizable. To overcome these limitations, the proposed method tries to converge to a cluster in the r-dimensional parameter space in which the design specifications including the specified optimality, periodicity, stability and robustness are satisfied. Thus, it eliminates the need for computationally expensive bifurcation studies to locate stable, periodic parameter regimes before optimization. The present method is based on a hybrid scheme which involves the algebraic form of the governing equations in screening phase and its differential form in the selection phase. In the screening phase, force and energy balance conditions are used to rephrase the nonlinear governing equations in terms of the design parameter vector. These rephrased equations are reduced to algebraic form using a harmonic balance procedure which also specifies the desired amplitude and frequency of the response. An error norm based on this algebraic form is defined and is used to contract the search bounds in the parameter space leading to convergence to a cluster. The selection phase of the algorithm uses shooting method coupled with evaluation of Floquet multipliers to retain only those vectors in the arrived cluster yielding stable periodic solutions. The method is validated with Den Hartog's vibration absorbers and is then applied to vibration absorbers with material nonlinearity and vibration isolators with geometric nonlinearity. In both the cases, the converged cluster is shown to yield stable, periodic responses satisfying the amplitude condition. Parametric perturbation studies are conducted on the cluster to illustrate its robustness. The use of algebraic form of governing equations in the screening phase drastically reduces the computational time needed to converge to the cluster. The fact that the present method converges to a cluster in the parameter space rather than to a single parameter value offers the designer more freedom to choose the design vector from inside the cluster. It also ensures that the design is robust to small changes in parameter values.
Improving the measurement and acoustic performance of transparent face masks and shields
Authors: Cox Trevor J. , Dodgson George , Harris Lara , Perugia Emanuele , Stone Michael A. , Walsh Michael
Published: April 2022

Opaque face masks harm communication by preventing speech-reading (lip-reading) and attenuating high-frequency sound. Although transparent masks and shields (visors) with clear plastic inserts allow speech-reading, they usually create more sound attenuation than opaque masks. Consequently, an iterative process was undertaken to create a better design, and the instructions to make it are published. The experiments showed that lowering the mass of the plastic inserts decreases the high-frequency sound attenuation. A shield with a clear thermoplastic polyurethane (TPU) panel had an insertion loss of (2.0 ± 1.1) dB for 1.25–8 kHz, which improves on previous designs that had attenuations of 11.9 dB and above. A cloth mask with a TPU insert was designed and had an insertion loss of (4.6 ± 2.3) dB for 2–8 kHz, which is better than the 9–22 dB reported previously in the literature. The speech intelligibility index was also evaluated. Investigations to improve measurement protocols that use either mannikins or human talkers were undertaken. Manufacturing variability and inconsistency of human speaking were greater sources of experimental error than fitting differences. It was shown that measurements from a mannikin could match those from humans if insertion losses from four human talkers were averaged.
Shoulder Rotational Strength and Range of Motion in Unilateral and Bilateral Overhead Elite Athletes
Authors: Drigny Joffrey , Guermont Henri , Reboursière Emmanuel , Gauthier Antoine
Published: April 2022

Context: Overhead athletes place tremendous demands on the shoulder complex, which result in adaptive kinematics but potential susceptibility to injury. This study aimed to compare shoulder glenohumeral range of motion (ROM) and rotator muscles strength in bilateral and unilateral overhead sports. Design: Cross-sectional study; secondary care. Methods: Forty-two elite athletes (17.7 [4.5] y; 42.9% female), including 18 swimmers and 24 badminton players, were included. Preseason glenohumeral rotation ROM and isokinetic shoulder internal and external rotator muscles strength was tested (60°·s−1). Bilateral (nondominant:dominant) and agonist:antagonist (external rotator:internal rotator) conventional and functional deceleration ratios (eccentric to concentric) were calculated. The impact of sport and number of competitive years on shoulder ROM and strength was tested. Results: Badminton players had greater glenohumeral internal rotation deficit, total ROM deficit, and lower bilateral strength ratio than swimmers (P < .050). Rotational strength was positively associated with the competitive years, but greater in swimmers (P < .050) and on the internal rotator (P < .001). The functional deceleration ratio was negatively associated with the competitive years on the dominant side in swimmers and for both sides in badminton. Conclusions: Unilateral overhead athletes had greater ROM and rotational strength asymmetries than bilateral athletes. Interestingly, the functional deceleration ratio was lower over time on the dominant shoulder for both sports, but, surprisingly, also on the nondominant shoulder in badminton, potentially creating a greater risk for shoulder injuries.
Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca
2+
efflux and disrupted by PSEN1 loss of function
Authors: Lie Pearl P. Y. , Yoo Lang , Goulbourne Chris N. , Berg Martin J. , Stavrides Philip , Huo Chunfeng , Lee Ju-Hyun , Nixon Ralph A.
Published: April 2022

Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels—an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive “inside-out” TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in
PSEN1
knockout neurons. Our results, including features demonstrated in Alzheimer-mutant
PSEN1
knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.
Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy
Authors: Ng Thomas S. C. , Hu Huiyu , Kronister Stefan , Lee Chanseo , Li Ran , Gerosa Luca , Stopka Sylwia A. , Burgenske Danielle M. , Khurana Ishaan , Regan Michael S. , Vallabhaneni Sreeram , Putta Niharika , Scott Ella , Matvey Dylan , Giobbie-Hurder Anita , Kohler Rainer H. , Sarkaria Jann N. , Parangi Sareh , Sorger Peter K. , Agar Nathalie Y. R. , Jacene Heather A. , Sullivan Ryan J. , Buchbinder Elizabeth , Mikula Hannes , Weissleder Ralph , Miller Miles A.
Published: April 2022

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non–small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.
In situ temperature measurements in sooting methane/air flames using synchrotron x-ray fluorescence of seeded krypton atoms
Authors: Montgomery Matthew J. , Kwon Hyunguk , Kastengren Alan L. , Pfefferle Lisa D. , Sikes Travis , Tranter Robert S. , Xuan Yuan , McEnally Charles S.
Published: April 2022

Synchrotron x-ray fluorescence has been used to measure temperatures in optically dense gases where traditional methods would fail. These data provide a benchmark for stringent tests of computational fluid dynamics models for complex systems where physical and chemical processes are intimately linked. The experiments measured krypton number densities in a sooting, atmospheric pressure, nonpremixed coflow flame that is widely used in combustion research. The experiments not only form targets for the models, but the simulations also identify potential sources of uncertainties in the measurements, allowing for future improvements.
Comment on “Evidence of prehistoric human activity in the Falkland Islands”
Authors: Clark T. J. , Newton Jason , Wakefield Ewan D.
Published: April 2022

Stable isotopes from archaic Falkland Islands wolves (
Dusicyon australis
) indicate a high trophic, marine diet. Hamley
et al.
argue that this is consistent with mutualism with Yaghan people. However, most
D. australis
had similar isotopic signatures in the European era, despite human persecution. These data therefore neither support nor refute human-mediated introduction of
D. australis
to the Falklands.
Massive atrial myxoma presenting with unexplained haemoptysis
Authors: Tsagkridi Aliki , Keenan Niall , Keramida Kalliopi , Anderson Jonathan
Published: April 2022

Cardiac myxomas are scarce and their clinical manifestations can often be misdiagnosed or confused with other medical conditions. However, early diagnosis and surgical resection can prevent devastating complications of myxomas.

We herein describe a case of a huge left atrial myxoma of a female patient in her late 30s. What makes our case unique, apart from the massive size of the myxoma, is the unusual clinical presentation with incessant cough and haemoptysis for more than 6 months. The diagnosis was made by echocardiography and cardiac MR and successful surgical resection was performed with good long-term outcome.
Response inBRCA1mutation carrier with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX
Authors: Campoverde Leticia Estefania , Batalini Felipe , Bulushi Yarab , Bullock Andrea
Published: April 2022

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli’s disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour aBRCA1germline mutation. She had palliative chemotherapy, initially with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin, and then FOLFIRI and capecitabine, achieving a sustained near-complete response for at least 86 months. Chemotherapy was eventually discontinued when she was diagnosed with a tongue squamous cell carcinoma. Despite withholding systemic therapy, she has maintained a durable response. This is the first report in the English literature showing a sustained duration of response in a patient with PDAC and BRCA1germline mutation.
Trends in indirect liver function marker testing in Wales from 2000 to 2017 and their association with age and sex: an observational study
Authors: Hill Trevor Alexander , Crooks Colin John , West Joe , Morling Joanne R
Published: April 2022

Objective

If non-invasive markers of liver fibrosis were recorded frequently enough in clinical practice, it might be feasible to use them for opportunistic community screening for liver disease. We aimed to determine their current pattern of usage in the national primary care population in Wales.

Design

Using the Secure Anonymised Information Linkage (SAIL) Databank at Swansea University (2000–2017), we quantified the frequency of common liver blood tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count and albumin) used in fibrosis marker algorithms. We examined measurement variation by age and sex.

Results

During the 18-year study period, there were 2 145 178 adult patients with at least one blood test available for analysis. Over the study period, the percentage of SAIL patients receiving an ALT test in each year increased from 2% to 33%, with platelet count and albumin measurement increasing by a similar factor. AST testing, although initially rising, had decreased to 1% by the end of the study. AST and ALT values varied by age and sex, particularly in males with the upper normal range of ALT values decreasing rapidly from 90 U/L at age 30 to 45 U/L by age 80.

Conclusion

The reduction in AST testing to only 1% of the adult population limits the use of many non-invasive liver marker algorithms. To enable widespread screening, alternative algorithms for liver fibrosis that do not depend on AST should be developed. Liver fibrosis markers should be modified to include age-specific and sex-specific normal ranges.
Economic burden of low physical activity and high sedentary behaviour in Finland
Authors: Kolu Päivi , Kari Jaana T , Raitanen Jani , Sievänen Harri , Tokola Kari , Havas Eino , Pehkonen Jaakko , Tammelin Tuija H , Pahkala Katja , Hutri-Kähönen Nina , Raitakari Olli T , Vasankari Tommi
Published: April 2022

Background

Low physical activity and high sedentary behaviour are unquestionably relevant for public health while also increasing direct and indirect costs.

Methods

The authors examined the direct and indirect costs attributable to low physical activity and high sedentary behaviour in Finland in 2017. Costs related to major non-communicable diseases drawn from Finnish registries covered direct costs (outpatient visits, days of inpatient care, medication and institutional eldercare) and indirect costs (sickness-related absences, disability pensions, unemployment benefits, all-cause mortality and losses of income tax revenue). Prevalences of low physical activity and high sedentary behaviour (≥8 hours per 16 waking hours) were based on self-reports among adolescents or accelerometer data among adults and the elderly from three Finnish population studies: FINFIT 2017, Health 2011 and the Cardiovascular Risk in Young Finns Study. Cost calculations used adjusted population attributable fractions (PAF) and regression models. Total annual costs were obtained by multiplying PAF by the total costs of the given disease.

Results

The total costs of low physical activity in Finland in 2017 came to approximately €3.2 billion, of which direct costs accounted for €683 million and indirect ones for €2.5 billion. Costs attributable to high sedentary behaviour totalled roughly €1.5 billion.

Conclusion

The findings suggest that low physical activity and high sedentary behaviour levels create substantial societal costs. Therefore, actions intended to increase physical activity and reduce excessive sedentary behaviour throughout life may yield not only better health but also considerable savings to society.
High cumulative risk of colorectal cancers and desmoid tumours and fibromatosis in South Asian APC mutation carriers
Authors: Ashar Shivani , Lipsa Anuja , Khan Nikhat , Sarin Rajiv
Published: April 2022

Management of familial adenomatous polyposis (FAP) is guided by the cumulative risk of colorectal cancer (CRC) and aggressive fibromatosis/desmoid (AF/D). The first non-Caucasian FAP cohort with cumulative risk estimates for CRC and AF/D shows distinct differences with the Caucasian and other Asian cohorts. The strong correlation between the adenomatous polyposis coli (APC) mutation location with the FAP phenotype and the geoethnic differences in APC mutation spectrum, genetic constitution, lifestyle and sporadic CRC rates, mandates the use of population-specific cumulative risk estimates for CRC and desmoid for counselling and risk management. On genotype–phenotype correlation in 83 individuals with classical FAP and a confirmed pathogenic/likely Pathogenic (P/LP) APC variant (n=76) or obligate carrier of the family variant (n=7), we observed a high cumulative CRC risk of 40% and 85% by 40 and 60 years, respectively. The observed 30% cumulative risk by 50 years for desmoids was higher than previous European and Asian cohorts and was significantly associated with prophylactic surgery (OR: 4.58, 95% CI 1.06 to 19.78) and APC mutation 3′ of codon 1309 (OR: 13.07, 95% CI 3.58 to 47.56) and also 3′ of codon 1444 (OR: 8.0, 95% CI 1.83 to 34.94). Global cooperation is required to establish FAP genotype–phenotype associations and population-specific risk estimates to guide genetic counselling and risk management.
Effect of composition and microstructure on the rusting of MS rebars and ultimately their impact on mechanical behavior
Authors: Shazad Atif , Jadoon Junaid , Uzair Muhammad , Akhtar Maaz , Shakoor Abdul , Muzamil Muhammad , Sattar Mohsin
Published: April 2022

Rebar steel is used for reinforcement to aid concrete because concrete does not sustain tension. Thermomechanical treatment is an advanced manufacturing technique for rebar production, but rusting problems emerged in the local steel industry. Raw material sampling included ingot casting (IC) and continuous casting (CC). IC samples corroded more frequently than CC samples. Spectroscopy indicated a small amount of chromium and an improper ratio of manganese to sulfur in IC samples. The improper ratio of manganese to sulfur in IC samples promoted hot cracking at grain boundaries, which resulted in intergranular corrosion. The microstructural results of G40 (air cooled) and G60 (water cooled) showed ferrite and martensite in different proportions. The deformed ferrite in G60 indicated inclination to corrosion, and no proper stable layer of martensite was found. The percentage of martensite was not enough to retaliate against intergranular corrosion. Highly pressurized water initiated pitting corrosion due to the formation of small pits on the surface. Tensile testing revealed 10% reduction in ultimate strength, 8% reduction in yield strength, and 30% reduction in percentage of elongation of corroded samples. Environmental study revealed that the humidity level in the industry was greater than in the laboratory space. High values of SOxand NOxemission revealed the involvement of the environment in the deterioration of the product surface.
Entanglement entropy and Page curve of black holes with island in massive gravity
Authors: Nam Cao H.
Published: April 2022

By applying the island rule proposed recently, we compute the entanglement entropy of Hawking radiation and study the Page curve for the eternal black holes in massive gravity. We investigate for both the neutral and charged black holes which the corresponding results of Schwarzschild and Reissner–Nordström black holes are restored in the limit of massless graviton. We show for the neutral and non-extremal charged black holes that the island is not formed at the early times of the evaporation and hence the entanglement entropy increases linearly in time. However, for the extremal charged black hole, the calculation of the entanglement entropy at the early times without the island is ill-defined because the metric is divergent at the curvature singularity. This implies that new physics in the UV region must be taken into account to make the metric behaving smoothly at the very short distances. At the late times, with the emergence of one island near the event horizon, the entanglement entropy is saturated by the Bekenstein–Hawking entropy of black holes. In addition, we analyze the impact of massive gravity parameters on the size of island, the entanglement entropy, the Page time, and the scrambling time in detail.