bluuebunny/crossref_metadata_2025 huggingface dataset:
Un-suturing Westphalian IR via non-Western literature: A Grey Man (1963)
Authors: Cho Young Chul , Seo Jungmin
Published: January 2024

This paper aims to un-suture common-sense assumptions based on Westphalian International Relations (IR) from South Korea’s non-essentialist and situated perspective, in the context of decolonising IR. Towards this end, the paper methodologically investigates a South Korean novel, A Grey Man, published in 1963 during South Korea’s early post-colonial period at the height of the Cold War. Using a non-Western novel to conduct a contrapuntal reading of Westphalian IR, this paper constructs a different type of worlding, conceptualising ‘the international’ through ‘the cultural’. It explores the following questions: How do ‘yellow negroes’ (the subject race) make sense of themselves and their roles and life-modes in a world defined for them by the white West (the master race)? How do yellow negroes understand and respond to the white West, which is hegemonic in world politics and history? In what ways does the protagonist of A Grey Man resist, engage with, and relate to the hegemonic West, which he has already internalised? In addressing these questions, the paper attempts to access different IR words to think with, such as race, white supremacy, intimacy without equality, sarcastic empathy, and disengagement. These provide an arena in which we can think otherwise, while un-suturing dominant Westphalian IR thinking.
Tailoring the motion planning of humanoids in complex arena: a regression-firefly-based approach
Authors: Sahu Chinmaya , Parhi Dayal R. , Muni Manoj Kumar , Kamat Saurabh Sameer
Published: January 2024

In the current investigation, a two-stage hybridization model has been used for the motion planning of humanoids in complex environmental conditions using regression analysis and the firefly algorithm. In the first step, sensory outputs are fed to the regression model, and an initial turning angle (ITA) is obtained. In the second step, the ITA is again fed as input to the firefly model along with other required inputs, and the final turning angle (FTA) is obtained. The FTA serves as the guiding parameter for the humanoids to reach their desired destinations. The developed motion planning scheme has been implemented on NAO humanoid robots in simulation and experimental platforms. A Petri-Net control strategy has been integrated along with the hybrid scheme while negotiating multiple humanoids in a common platform. The results obtained from the motion planning analysis in simulation and experimental arenas are compared against each other in terms of selected navigational parameters and observed satisfactory agreements. Finally, the proposed hybrid controller is also tested against another standard navigational model and substantial enhancement in the performance has been noticed.
Design, modeling, and control of a novel soft-rigid knee joint robot for assisting motion
Authors: Li Yinan , Wang Yuxuan , Yuan Shaoke , Fei Yanqiong
Published: January 2024

This paper presents the design, modeling, and control of a novel soft-rigid knee joint robot (SR-KR) for assisting motion. SR-KR is proposed to assist patients with knee joint injuries conducting gait training and completing walking movements. SR-KR consists of a novel soft-rigid bidirectional curl actuator, a thigh clamping structure, and a crus clamping structure. The actuating part of SR-KR is composed of soft materials, which ensures the wearing comfort and safety, while the wearing parts contain rigid structure, which ensures the efficient transmission of torque. The bending deformation model of SR-KR is established, which reveal the relationship among SR-KR’s bending curvature, working pressure, and output torque. Experiments show that SR-KR can provide more than 26.3 Nm torque for knee joint motion in human gait range. A double closed loop servo control system including attitude servo and pressure servo is built to better apply SR-KR. Mechanical property test, trajectory-driven test, and lower limb wearing test have been conducted, which show that SR-KR has ability to assist in lower limb motion and has potential in the fields of rehabilitation and human enhancement.
A novel Human-Aware Navigation algorithm based on behavioral intention cognition
Authors: Li Jiahao , Zhang Fuhai , Fu Yili
Published: January 2024

In order to ensure safe and comfortable human–robot navigation in close proximity, it is imperative for robots to possess the capability to understand human behavioral intention. With this objective in mind, this paper introduces a Human-Aware Navigation (HAN) algorithm. The HAN system combines insights from studies on human detection, social behavioral model, and behavior prediction, all while incorporating social distance considerations. This information is integrated into a layer dedicated to human behavior intention cognition, achieved through the fusion of data from laser radar and Kinect sensors, employing Gaussian functions to account for individual private space and movement trend. To cater to the mapping requirements of the HAN system, we have reduced the computational complexity associated with traditional multilayer cost map by implementing a “first-come, first-served” expansion method. Subsequently, we have enhanced the trajectory optimization equation by incorporating an improved dynamic triangle window method that integrates human behavior intention cognition, leading to the determination of an appropriate trajectory for the robot. Finally, experimental evaluations have been conducted to assess and validate the efficacy of the human behavior intention cognition and the HAN system. The results clearly demonstrate that the HAN system outperforms the traditional Dynamic Window Approach algorithm in ensuring the safety and comfort of humans in human–robot coexistence environments.
Enjoyment of music and GCSE uptake: survey findings from three North East schools in England
Authors: Whitford Helen , Kokotsaki Dimitra
Published: January 2024

In recent years, music education has seen a decline in the number of students choosing to continue their studies at Key Stage 4 (14- to 16-year-old students) and choose music as a GCSE option in England. Whilst the English Baccalaureate (EBacc), a school performance measure which excludes the arts, has come under much scrutiny as to its impact on school music, enjoyment and the perceived importance of music lessons could also be contributing factors to low uptake. This paper presents student survey findings from the first part of a two-phase project that was based on a qualitatively driven mixed-method research design. Findings demonstrated that a decline in enjoyment and in the importance attributed to school music occurred in the first three years of lower secondary school (Key Stage 3). The enjoyment of school music was linked with the students’ engagement with practical components of music making, and its importance was mostly equated with future employment opportunities. The findings are discussed in terms of their practical implications in the teaching of music in secondary schools.
Love for a handsome man requires a lot of friends: Sociability practices related to romance games (Otome Games) in Japan
Authors: Giard Agnès
Published: January 2024

Japan is the world’s largest producer of love simulation games, revealing a curious feature: these games, in theory, assign female players to the unique task of seducing a male character, but, in reality, they promote the establishment of a network of friendship between women. Love cannot be achieved if this network is not carefully woven both in play and in real life. Based on the analysis of this double dynamics, outwardly contradictory, I would like to advance the following hypothesis: that such games enable their users to ‘outsmart’ gender expectations. These games, called otome games, became popular in the context of a national panic related to the declining birthrate: they target the market of women who – living alone or with their parents – are held responsible for the future shortfall of the system. These new generations of women don’t start a family. They have no children. How do they manage to ward off exclusion and stigma? The study will focus on the strategies collectively devised to turn otome games into an identity-building tool, promoting friendship between players as a means of resistance against social norms.
How effective psychological treatments work: mechanisms of change in cognitive behavioural therapy and beyond
Authors: Salkovskis Paul M. , Sighvatsson Magnus Blondahl , Sigurdsson Jon Fridrik
Published: January 2024

Background:

Cognitive behavioural therapy (CBT) has, in the space of 50 years, evolved into the dominant modality in psychological therapy. Mechanism/s of change remain unclear, however.

Aims:

In this paper, we will describe key features of CBT that account for the pace of past and future developments, with a view to identifying candidates for mechanism of change. We also highlight the distinction between ‘common elements’ and ‘mechanisms of change’ in psychological treatment.

Method:

The history of how behaviour therapy and cognitive therapy developed are considered, culminating in the wide range of strategies which now fall under the heading of cognitive behavioural therapy (CBT). We consider how the empirical grounding of CBT has led to the massive proliferation of effective treatment strategies. We then consider the relationship between ‘common factors’ and ‘mechanisms of change’, and propose that a particular type of psychological flexibility is the mechanism of change not only in CBT but also effective psychological therapies in general.

Conclusion:

Good psychological therapies should ultimately involve supporting people experiencing psychological difficulties to understand where and how they have become ‘stuck’ in terms of factors involved in maintaining distress and impairment. A shared understanding is then evaluated and tested with the intention of empowering and enabling them to respond more flexibly and thereby reclaim their life.
Roadmaps to managed competition: to what extent does South Africa meet the preconditions for equity and efficiency?
Authors: van den Heever Alex
Published: January 2024

South Africa offers universal health coverage through large public and private systems. The private system is characterised by a regulated market for health insurance, referred to domestically as medical schemes. From 2000, the private system was undergoing a reform process consistent with theoretical approaches for regulated competition for health insurance. However, from 2008, the reform process was interrupted, leaving in place a partial framework which included open enrolment, community rating and regulated minimum benefits but excluded, inter alia, risk equalisation. The incomplete reform, however, provides an opportunity to examine the system outcomes that result from a partial approach. This paper therefore reviews the system outcomes of the partial reform using a descriptive data analysis. The findings then inform an evaluation of the extent to which the preconditions for regulated competition have been met as indicated by the theory of regulated competition in healthcare. The paper therefore highlights the areas where regulatory interventions need to be prioritised in South Africa to achieve the objectives of regulatory competition that are able to achieve access, fairness and efficiency. The analysis points to significant failures at the level of health insurance competition in South Africa with resulting outcomes consistent with the theory of regulated competition.
Norwegian Adolescents in the Initial Stages of COVID-19 Restrictions
Authors: Hygen Beate W. , Skalicka Vera , Coplan Robert J. , von Soest Tilmann , Fredriksen Eivor , Bekkhus Mona
Published: January 2024

Abstract: In response to the COVID-19 pandemic outbreak in March 2020, the Norwegian government closed schools and limited leisure activities. In this cross-sectional study, we examined how different types of digital versus in-person social interactions and digital media use were associated with loneliness and mental health problems among adolescents during the initial COVID-19 lockdown. Participants ( N = 703, 79.7% girls , Mage  = 17.3 years) completed a questionnaire assessing loneliness, mental health problems, digital media use, and in-person interactions. Both in-person and digital social interaction (texting) with friends were negatively associated with adolescents’ mental health problems and loneliness. By contrast, time spent alone on screen and on social media was positively related to mental health problems. The findings highlight that during the first weeks of the pandemic and of social distancing, increased interactions (either in-person or digital) among adolescents and their friends coincided with lower levels of mental health problems and less loneliness.
Bleeding-Heart Horror Fans
Authors: Scrivner Coltan
Published: January 2024

Abstract: The horror genre portrays some of the most graphic and violent scenes in media. How and why some people find enjoyment in such a graphic genre is an age-old question. One hypothesis is that people lower in prosocial traits such as empathy and compassion are more likely to enjoy horror. We found evidence against this hypothesis across three studies. Study 1 demonstrated that enjoyment of horror movies was unrelated to affective empathy, negatively associated with coldheartedness, and positively associated with cognitive empathy. A preregistered follow-up study found that measures of empathy and coldheartedness were unrelated to how many horror movies a participant had seen. In Study 3, enjoyment of horror movies was unrelated to the amount of money a participant decided to donate to a less fortunate participant. These findings contradict beliefs from the public about horror fans possessing lower levels of prosocial traits such as empathy and compassion. They also put into question findings from older studies about the relationship between empathy and enjoyment of horror media.
A Forecast Test for Reducing Dynamical Dimensionality of Model Emulators
Authors: Xu Tongtong , Newman Matthew , Alexander Michael A. , Capotondi Antonietta
Published: January 2024

The climate system can be numerically represented by a set of physically based dynamical equations whose solution requires substantial computational resources. This makes computationally efficient, low dimensional emulators that simulate trajectories of the underlying dynamical system an attractive alternative for model evaluation and diagnosis. We suggest that since such an emulator must adequately capture anomaly evolution, its construction should employ a grid search technique where maximum forecast skill determines the best reference model. In this study, we demonstrate this approach by testing different bases used to construct a Linear Inverse Model (LIM), a stochastically forced multivariate linear model that has often been used to represent the evolution of coarse‐grained climate anomalies in both models and observations. LIM state vectors are typically represented in a basis of the leading Empirical Orthogonal Functions (EOFs), but while dominant large‐scale climate variations often are captured by a subset of these statistical patterns, key precursor dynamics involving relatively small scales are not. An alternative approach is balanced truncation, where the dynamical system is transformed into its Hankel space, whose modes span both precursors and their subsequent responses. Constructing EOF‐ and Hankel‐based LIMs from monthly observed anomalous Pacific sea surface temperatures, both for the 150‐year observational record and a perfect model study using 600 years of LIM output, we find that no balanced truncation model of any dimension can outperform an EOF‐based LIM whose dimension is chosen to maximize independent skill. However, the dynamics of a high‐dimensional EOF‐based LIM can be efficiently reproduced by far fewer Hankel modes.
Properties of Intense H‐Band Electromagnetic Ion Cyclotron Waves: Implications for Quasi‐Linear, Nonlinear, and Nonresonant Wave‐Particle Interactions
Authors: Shi Xiaofei , Artemyev Anton , Zhang Xiao‐Jia , Mourenas Didier , An Xin , Angelopoulos Vassilis
Published: January 2024

Resonant interactions between relativistic electrons and electromagnetic ion cyclotron (EMIC) waves provide an effective loss mechanism for this important electron population in the outer radiation belt. The diffusive regime of electron scattering and loss has been well incorporated into radiation belt models within the framework of the quasi‐linear diffusion theory, whereas the nonlinear regime has been mostly studied with test particle simulations. There is also a less investigated, nonresonant regime of electron scattering by EMIC waves. All three regimes should be present, depending on the EMIC waves and ambient plasma properties, but the occurrence rates of these regimes have not been previously quantified. This study provides a statistical investigation of the most important EMIC wave‐packet characteristics for the diffusive, nonlinear, and nonresonant regimes of electron scattering. We utilize 3 years of observations to derive distributions of wave amplitudes, wave‐packet sizes, and rates of frequency variations within individual wave‐packets. We demonstrate that EMIC waves typically propagate as wave‐packets with ∼10 wave periods each, and that ∼3–10% of such wave‐packets can reach the regime of nonlinear resonant interaction with 2–6 MeV electrons. We show that EMIC frequency variations within wave‐packets reach 50–100% of the center frequency, corresponding to a significant high‐frequency tail in their wave power spectrum. We explore the consequences of these wave‐packet characteristics for high and low energy electron precipitation by H‐band EMIC waves and for the relative importance of quasi‐linear and nonlinear regimes of wave‐particle interactions.
Assessing Empirical Components in Wave Breaking and Rollers Through Model Comparison of Radiation Stress and Vortex Force
Authors: Wu Yuefeng , Wu Yongsheng , Zhang Qinghe , Ji Chao
Published: January 2024

As incoming waves approach shallow water, they break and result in nearshore currents. The assessment of the wave‐induced nearshore currents often relies on the application of radiation stress (RS) and vortex force (VF) in circulation models, both of which incorporate empirical components to describe wave breaking and wave rollers. In this study, we compared a recent 3D RS formulation and a VF formulation by assessing the modeled cross‐shore velocities against the measured counterparts from the LIP11D and Duck’94 experiments. The comparison results indicate that the RS model performs better in LIP11D, whereas the VF model exhibits better with respect to Duck’94. Using momentum balance analysis, we found that the cross‐shore velocities were dominated by the breaking term (representing the RS terms and non‐conservative breaking term in the RS and VF models, respectively) and the roller term. The breaking term generates undertow currents across the entire surf zone. The roller term cooperates with the breaking term in the inner surf zone, but counteracts the breaking term and tends to trigger unrealistic offshore currents at the water surface in the outer surf zone. Further analysis reveals that the RS and VF formulations can simulate almost identical velocity results by adjusting the vertical distribution of the breaking and roller terms. Overall, this study indicates that both the RS and VF formulations are effective in evaluating wave effects on the cross‐shore currents, and empirical components in the breaking and roller terms are important for modeling cross‐shore velocities.
India’s Disadvantaged Groups Face More Air Pollution
Authors: Padmanaban Deepa
Published: January 2024

A new study investigates disparities in air pollution exposure across different socially disadvantaged groups in India.
Modification of immune cell-derived exosomes for enhanced cancer immunotherapy: current advances and therapeutic applications
Authors: Jung Inseong , Shin Sanghee , Baek Moon-Chang , Yea Kyungmoo
Published: January 2024

Cancer immunotherapy has revolutionized the approach to cancer treatment of malignant tumors by harnessing the body’s immune system to selectively target cancer cells. Despite remarkable advances, there are still challenges in achieving successful clinical responses. Recent evidence suggests that immune cell-derived exosomes modulate the immune system to generate effective antitumor immune responses, making them a cutting-edge therapeutic strategy. However, natural exosomes are limited in clinical application due to their low drug delivery efficiency and insufficient antitumor capacity. Technological advancements have allowed exosome modifications to magnify their intrinsic functions, load different therapeutic cargoes, and preferentially target tumor sites. These engineered exosomes exert potent antitumor effects and have great potential for cancer immunotherapy. In this review, we describe ingenious modification strategies to attain the desired performance. Moreover, we systematically summarize the tumor-controlling properties of engineered immune cell-derived exosomes in innate and adaptive immunity. Collectively, this review provides a comprehensive and intuitive guide for harnessing the potential of modified immune cell-derived exosome-based approaches, offering valuable strategies to enhance and optimize cancer immunotherapy.
Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma
Authors: Li Xun , Zhang Cheng-Cheng , Lin Xiao-Tong , Zhang Jie , Zhang Yu-Jun , Yu Hong-Qiang , Liu Ze-Yu , Gong Yi , Zhang Lei-Da , Xie Chuan-Ming
Published: January 2024

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.
Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies
Authors: Seo Dong-oh , Holtzman David M.
Published: January 2024

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.
Pathological phenotypes of astrocytes in Alzheimer’s disease
Authors: Kim Junhyung , Yoo Ik Dong , Lim Jaejoon , Moon Jong-Seok
Published: January 2024

Astrocytes are involved in various processes in the central nervous system (CNS). As the most abundant cell type in the CNS, astrocytes play an essential role in neuronal maintenance and support, synaptic activity, neuronal metabolism, and amyloid-beta (Aβ) clearance. Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral impairment. The transformation of astrocytes is involved in various neurodegenerative diseases, such as AD. Since astrocytes have functional diversity and morphological and physiological heterogeneity in the CNS, AD-related astrocytes might show various pathological phenotypes during AD. Astrocytes developing pathological phenotypes could contribute to AD progression. In this review, we provide an overview of the pathological phenotypes of astrocytes in the context of AD, highlighting recent findings in human and mouse AD.
Astrocytes in the adult dentate gyrus—balance between adult and developmental tasks
Authors: Chalmers Nicholas , Masouti Evangelia , Beckervordersandforth Ruth
Published: January 2024

Astrocytes, a major glial cell type in the brain, are indispensable for the integration, maintenance and survival of neurons during development and adulthood. Both life phases make specific demands on the molecular and physiological properties of astrocytes, and most research projects traditionally focus on either developmental or adult astrocyte functions. In most brain regions, the generation of brain cells and the establishment of neural circuits ends with postnatal development. However, few neurogenic niches exist in the adult brain in which new neurons and glial cells are produced lifelong, and the integration of new cells into functional circuits represent a very special form of plasticity. Consequently, in the neurogenic niche, the astrocytes must be equipped to execute both mature and developmental tasks in order to integrate newborn neurons into the circuit and yet maintain overall homeostasis without affecting the preexisting neurons. In this review, we focus on astrocytes of the hippocampal dentate gyrus (DG), and discuss specific features of the astrocytic compartment that may allow the execution of both tasks. Firstly, astrocytes of the adult DG are molecularly, morphologically and functionally diverse, and the distinct astrocytes subtypes are characterized by their localization to DG layers. This spatial separation may lead to a functional specification of astrocytes subtypes according to the neuronal structures they are embedded in, hence a division of labor. Secondly, the astrocytic compartment is not static, but steadily increasing in numbers due to lifelong astrogenesis. Interestingly, astrogenesis can adapt to environmental and behavioral stimuli, revealing an unexpected astrocyte dynamic that allows the niche to adopt to changing demands. The diversity and dynamic of astrocytes in the adult DG implicate a vital contribution to hippocampal plasticity and represent an interesting model to uncover mechanisms how astrocytes simultaneously fulfill developmental and adult tasks.
Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer’s disease
Authors: Van Hulle Carol , Ince Selvi , Okonkwo Ozioma C. , Bendlin Barbara B. , Johnson Sterling C. , Carlsson Cynthia M. , Asthana Sanjay , Love Seth , Blennow Kaj , Zetterberg Henrik , Scott Miners J.
Published: January 2024

Breakdown of the neurovascular unit is associated with blood-brain barrier (BBB) leakiness contributing to cognitive decline and disease pathology in the early stages of Alzheimer’s disease (AD). Vascular stability depends on angiopoietin-1 (ANGPT-1) signalling, antagonised by angiopoietin-2 (ANGPT-2) expressed upon endothelial injury. We examined the relationship between CSF ANGPT-2 and CSF markers of BBB leakiness and core AD biomarkers across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer’s Prevention or Wisconsin Alzheimer’s Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 20 participants with mild cognitive impairment (MCI), and 17 with AD); (iii) a neurologically normal cohort aged 23–78 years with paired CSF and serum samples. CSF ANGPT-2, sPDGFRβ, albumin and fibrinogen levels were measured by sandwich ELISA. In cohort (i), CSF ANGPT-2 was elevated in AD and correlated with CSF t-tau and p-tau181 but not Aβ42. ANGPT-2 also correlated positively with CSF sPDGFRβ and fibrinogen – markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT-2 was highest in MCI and correlated with CSF albumin in the CU and MCI cohorts but not in AD. CSF ANGPT-2 also correlated with CSF t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT-2 correlated strongly with the CSF/serum albumin ratio. Serum ANGPT-2 showed non-significant positive associations with CSF ANGPT-2 and the CSF/serum albumin ratio. Together, these data indicate that CSF and possibly serum ANGPT-2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT-2 as a biomarker of BBB damage in AD requires further study.
Protein tyrosine phosphatase PTPRO represses lung adenocarcinoma progression by inducing mitochondria-dependent apoptosis and restraining tumor metastasis
Authors: Dai Yuan , Shi Shuangshuang , Liu Hongda , Zhou Hong , Ding Wenqiu , Liu Chenyang , Jin Linling , Xie Weiping , Kong Hui , Zhang Qun
Published: January 2024

Emerging evidence indicates that protein activities regulated by receptor protein tyrosine phosphatases (RPTPs) are crucial for a variety of cellular processes, such as proliferation, apoptosis, and immunological response. Protein tyrosine phosphatase receptor type O (PTPRO), an RPTP, has been revealed as a putative suppressor in the development of particular tumors. However, the function and the underlying mechanisms of PTPRO in regulating of lung adenocarcinoma (LUAD) are not well understood. In this view, the present work investigated the role of PTPRO in LUAD. Analysis of 90 pairs of clinical LUAD specimens revealed significantly lower PTPRO levels in LUAD compared with adjacent non-tumor tissue, as well as a negative correlation of PTPRO expression with tumor size and TNM stage. Survival analyses demonstrated that PTPRO level can help stratify the prognosis of LUAD patients. Furthermore, PTPRO overexpression was found to suppress the progression of LUAD both in vitro and in vivo by inducing cell death via mitochondria-dependent apoptosis, downregulating protein expression of molecules (Bcl-2, Bax, caspase 3, cleaved-caspase 3/9, cleaved-PARP and Bid) essential in cell survival. Additionally, PTPRO decreased LUAD migration and invasion by regulating proteins involved in the epithelial-to-mesenchymal transition (E-cadherin, N-cadherin, and Snail). Moreover, PTPRO was shown to restrain JAK2/STAT3 signaling pathways. Expression of PTPRO was negatively correlated with p-JAK2, p-STAT3, Bcl-2, and Snail levels in LUAD tumor samples. Furthermore, the anti-tumor effect of PTPRO in LUAD was significant but compromised in STAT3-deficient cells. These data support the remarkable suppressive role of PTPRO in LUAD, which may represent a viable therapeutic target for LUAD patients.
Validity of European-centric cardiometabolic polygenic scores in multi-ancestry populations
Authors: Topriceanu Constantin-Cristian , Chaturvedi Nish , Mathur Rohini , Garfield Victoria
Published: January 2024

Polygenic scores (PGSs) provide an individual level estimate of genetic risk for any given disease. Since most PGSs have been derived from genome wide association studies (GWASs) conducted in populations of White European ancestry, their validity in other ancestry groups remains unconfirmed. This is especially relevant for cardiometabolic diseases which are known to disproportionately affect people of non-European ancestry. Thus, we aimed to evaluate the performance of PGSs for glycaemic traits (glycated haemoglobin, and type 1 and type 2 diabetes mellitus), cardiometabolic risk factors (body mass index, hypertension, high- and low-density lipoproteins, and total cholesterol and triglycerides) and cardiovascular diseases (including stroke and coronary artery disease) in people of White European, South Asian, and African Caribbean ethnicity in the UK Biobank. Whilst PGSs incorporated some GWAS data from multi-ethnic populations, the vast majority originated from White Europeans. For most outcomes, PGSs derived mostly from European populations had an overall better performance in White Europeans compared to South Asians and African Caribbeans. Thus, multi-ancestry GWAS data are needed to derive ancestry stratified PGSs to tackle health inequalities.
Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
Authors: Poli M. Cecilia , Rebolledo-Jaramillo Boris , Lagos Catalina , Orellana Joan , Moreno Gabriela , Martín Luz M. , Encina Gonzalo , Böhme Daniela , Faundes Víctor , Zavala M. Jesús , Hasbún Trinidad , Fischer Sara , Brito Florencia , Araya Diego , Lira Manuel , de la Cruz Javiera , Astudillo Camila , Lay-Son Guillermo , Cares Carolina , Aracena Mariana , Martin Esteban San , Coban-Akdemir Zeynep , Posey Jennifer E. , Lupski James R. , Repetto Gabriela M.
Published: January 2024

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
Ghrelin mediated cardioprotection using in vitro models of oxidative stress
Authors: Kok Cindy Y. , Ghossein George , Igoor Sindhu , Rao Renuka , Titus Tracy , Tsurusaki Shinya , Chong James JH. , Kizana Eddy
Published: January 2024

Ghrelin is commonly known as the ‘hunger hormone’ due to its role in stimulating food intake in humans. However, the roles of ghrelin extend beyond regulating hunger. Our aim was to investigate the ability of ghrelin to protect against hydrogen peroxide (H2O2), a reactive oxygen species commonly associated with cardiac injury. An in vitro model of oxidative stress was developed using H2O2 injured H9c2 cells. Despite lentiviral ghrelin overexpression, H9c2 cell viability and mitochondrial function were not protected following H2O2 injury. We found that H9c2 cells lack expression of the preproghrelin cleavage enzyme prohormone convertase 1 (encoded by PCSK1), required to convert ghrelin to its active form. In contrast, we found that primary rat cardiomyocytes do express PCSK1 and were protected from H2O2 injury by lentiviral ghrelin overexpression. In conclusion, we have shown that ghrelin expression can protect primary rat cardiomyocytes against H2O2, though this effect was not observed in other cell types tested.
Convergence of resistance and evolutionary responses in Escherichia coli and Salmonella enterica co-inhabiting chicken farms in China
Authors: Baker Michelle , Zhang Xibin , Maciel-Guerra Alexandre , Babaarslan Kubra , Dong Yinping , Wang Wei , Hu Yujie , Renney David , Liu Longhai , Li Hui , Hossain Maqsud , Heeb Stephan , Tong Zhiqin , Pearcy Nicole , Zhang Meimei , Geng Yingzhi , Zhao Li , Hao Zhihui , Senin Nicola , Chen Junshi , Peng Zixin , Li Fengqin , Dottorini Tania
Published: January 2024

Sharing of genetic elements among different pathogens and commensals inhabiting same hosts and environments has significant implications for antimicrobial resistance (AMR), especially in settings with high antimicrobial exposure. We analysed 661 Escherichia coli and Salmonella enterica isolates collected within and across hosts and environments, in 10 Chinese chicken farms over 2.5 years using data-mining methods. Most isolates within same hosts possessed the same clinically relevant AMR-carrying mobile genetic elements (plasmids: 70.6%, transposons: 78%), which also showed recent common evolution. Supervised machine learning classifiers revealed known and novel AMR-associated mutations and genes underlying resistance to 28 antimicrobials, primarily associated with resistance in E. coli and susceptibility in S. enterica. Many were essential and affected same metabolic processes in both species, albeit with varying degrees of phylogenetic penetration. Multi-modal strategies are crucial to investigate the interplay of mobilome, resistance and metabolism in cohabiting bacteria, especially in ecological settings where community-driven resistance selection occurs.
MENDER: fast and scalable tissue structure identification in spatial omics data
Authors: Yuan Zhiyuan
Published: January 2024

Tissue structure identification is a crucial task in spatial omics data analysis, for which increasingly complex models, such as Graph Neural Networks and Bayesian networks, are employed. However, whether increased model complexity can effectively lead to improved performance is a notable question in the field. Inspired by the consistent observation of cellular neighborhood structures across various spatial technologies, we propose Multi-range cEll coNtext DEciphereR (MENDER), for tissue structure identification. Applied on datasets of 3 brain regions and a whole-brain atlas, MENDER, with biology-driven design, offers substantial improvements over modern complex models while automatically aligning labels across slices, despite using much less running time than the second-fastest. MENDER’s identification power allows the uncovering of previously overlooked spatial domains that exhibit strong associations with brain aging. MENDER’s scalability makes it freely appliable on a million-level brain spatial atlas. MENDER’s discriminative power enables the differentiation of breast cancer patient subtypes obscured by single-cell analysis.
Direct translation of incoming retroviral genomes
Authors: Köppke Julia , Keller Luise-Elektra , Stuck Michelle , Arnow Nicolas D. , Bannert Norbert , Doellinger Joerg , Cingöz Oya
Published: January 2024

Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
The virulence regulator VirB from Shigella flexneri uses a CTP-dependent switch mechanism to activate gene expression
Authors: Jakob Sara , Steinchen Wieland , Hanßmann Juri , Rosum Julia , Langenfeld Katja , Osorio-Valeriano Manuel , Steube Niklas , Giammarinaro Pietro I. , Hochberg Georg K. A. , Glatter Timo , Bange Gert , Diepold Andreas , Thanbichler Martin
Published: January 2024

The transcriptional antisilencer VirB acts as a master regulator of virulence gene expression in the human pathogen Shigella flexneri. It binds DNA sequences (virS) upstream of VirB-dependent promoters and counteracts their silencing by the nucleoid-organizing protein H-NS. However, its precise mode of action remains unclear. Notably, VirB is not a classical transcription factor but related to ParB-type DNA-partitioning proteins, which have recently been recognized as DNA-sliding clamps using CTP binding and hydrolysis to control their DNA entry gate. Here, we show that VirB binds CTP, embraces DNA in a clamp-like fashion upon its CTP-dependent loading at virS sites and slides laterally on DNA after clamp closure. Mutations that prevent CTP-binding block VirB loading in vitro and abolish the formation of VirB nucleoprotein complexes as well as virulence gene expression in vivo. Thus, VirB represents a CTP-dependent molecular switch that uses a loading-and-sliding mechanism to control transcription during bacterial pathogenesis.
Proxy-analysis of the genetics of cognitive decline in Parkinson’s disease through polygenic scores
Authors: Faouzi Johann , Tan Manuela , Casse Fanny , Lesage Suzanne , Tesson Christelle , Brice Alexis , Mangone Graziella , Mariani Louise-Laure , Iwaki Hirotaka , Colliot Olivier , Pihlstrøm Lasse , Corvol Jean-Christophe
Published: January 2024

Cognitive decline is common in Parkinson’s disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achieve for outcome measures in PD. Taking an alternative approach, we computed 100 polygenic scores (PGS) related to cognitive, dementia, stroke, and brain anatomical phenotypes and investigated their association with cognitive decline in six longitudinal cohorts. The analysis was adjusted for age, sex, genetic ancestry, follow-up duration, GBA and APOE status. Then, we meta-analyzed five of these cohorts, comprising a total of 1702 PD participants with 6156 visits, using the Montreal Cognitive Assessment as a cognitive outcome measure. After correction for multiple comparisons, we found four PGS significantly associated with cognitive decline: intelligence (p = 5.26e–13), cognitive performance (p = 1.46e–12), educational attainment (p = 8.52e–10), and reasoning (p = 3.58e–5). Survival analyses highlighted an offset of several years between the first and last quartiles of PGS, with significant differences for the PGS of cognitive performance (5 years) and educational attainment (7 years). In conclusion, we found four PGS associated with cognitive decline in PD, all associated with general cognitive phenotypes. This study highlights the common genetic factors between cognitive decline in PD and the general population, and the importance of the participant’s cognitive reserve for cognitive outcome in PD.
Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial
Authors: Trudel Suzanne , McCurdy Arleigh , Louzada Martha L. , Parkin Stephen , White Darrell , Chu Michael P. , Kotb Rami , Mian Hira , Othman Ibraheem , Su Jiandong , Khan Aniba , Gul Engin , Reece Donna
Published: January 2024

Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody–drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody–drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478.