bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge-Aware Dual-Channel Graph Neural Networks For Denoising Recommendation
Authors: Zhang Hanwen , Wang Li-e , Sun Zhigang , Li Xianxian
Published: August 2023

Knowledge graph (KG) is introduced as side information into recommender systems, which can alleviate the sparsity and cold start problems in collaborative filtering. Existing studies mainly focus on modeling users’ historical behavior data and KG-based propagation. However, they have the limitation of ignoring noise information during recommendation. We consider that noise exists in two parts (i.e. KG and user-item interaction data). In this paper, we propose Knowledge-aware Dual-Channel Graph Neural Networks (KDGNN) to improve the recommendation performance by reducing the noise in the recommendation process. Specifically, (1) for the noise in KG, we design a personalized gating mechanism, namely dual-channel balancing mechanism, to block the propagation of redundant information in KG. (2) For the noise in user-item interaction data, we integrate personalized and knowledge-aware signals to capture user preferences fully and use personalized knowledge-aware attention to denoise user-item interaction data. Compared with existing KG-based methods, we aim to propose a knowledge-aware recommendation method from a new perspective of denoising. We perform performance analysis on three real-world datasets, and experiment results demonstrate that KDGNN achieves strongly competitive performance compared with several compelling state-of-the-art baselines.
The Promises and Pitfalls of Using (Mostly) Low-Touch Coaching Interventions to Improve College Student Outcomes
Authors: Oreopoulos Philip , Petronijevic Uros
Published: August 2023

We present results from a five-year effort to design promising virtual coaching interventions to improve college student achievement. Across nearly 20,000 students at three campuses, we find some improvement on study time, but no effect on academic outcomes. We interpret the results with unique survey data and a model of student effort. Treated students learn that more effort is needed to attain good grades and develop stronger preferences for high grades, but these effects are too small to translate into academic benefits. More comprehensive, social and better-timed interventions are needed for helping students outside the classroom.
Construction and application of a mCherry fluorescent labeling system for Stenotrophomonas AGS-1 from aerobic granular sludge
Authors: Meng Wei , Qiao Kai , Liu Fan , Hu Xuan , Liu Jia , Gao Yiyun , Zhu Jianrong
Published: August 2023

To elucidate the specific mechanism by which high-attachment bacteria promote aerobic granular sludge (AGS) formation, a red fluorescent protein mCherry-based biomarker system was developed in the high-attachment strain Stenotrophomonas AGS-1 from AGS. The fluorescent labeling system used plasmid-mediated mCherry expression driven by a Ptac constitutive promoter. mCherry-labeled AGS-1 had normal unimpaired growth, strong fluorescent signals, and good fluorescence imaging. Also, the mCherry labeling system had no effect on the attachment ability of AGS-1. In addition, mCherry-labeled AGS-1 maintained high plasmid stability, even after more than 100 generations. Notably, after the addition of mCherry-labeled AGS-1 into the activated sludge system, the mCherry fluorescence of the sludge system can be used as a good reflection of the relative amount of AGS-1. Moreover, the spatial distribution of mCherry-labeled AGS-1 in the sludge system could be visualized and remained clear even after 5 days by fluorescence imaging. These results revealed that the mCherry-based biomarker system would provide a valuable tool for labeling AGS-1 to monitor the spatial distribution and fate of AGS-1 in AGS, which would help to better understand the mechanism of AGS formation and facilitate the development of AGS technology.
Probing the physiological role of the plastid outer-envelope membrane using the oemiR plasmid collection
Authors: Schwenkert Serena , Lo Wing Tung , Szulc Beata , Yip Chun Kwan , Pratt Anna I , Cusack Siobhan A , Brandt Benjamin , Leister Dario , Kunz Hans-Henning
Published: August 2023

Plastids are the site of complex biochemical pathways, most prominently photosynthesis. The organelle evolved through endosymbiosis with a cyanobacterium, which is exemplified by the outer envelope membrane that harbors more than 40 proteins in Arabidopsis. Their evolutionary conservation indicates high significance for plant cell function. While a few proteins are well-studied as part of the protein translocon complex the majority of outer envelope protein functions is unclear. Gaining a deeper functional understanding has been complicated by the lack of observable loss-of-function mutant phenotypes, which is often rooted in functional genetic redundancy. Therefore, we designed outer envelope-specific artificial micro RNAs (oemiRs) capable of downregulating transcripts from several loci simultaneously. We successfully tested oemiR function by performing a proof-of-concept screen for pale and cold-sensitive mutants. An in-depth analysis of pale mutant alleles deficient in the translocon component TOC75 using proteomics provided new insights into putative compensatory import pathways. The cold stress screen not only recapitulated 3 previously known phenotypes of cold-sensitive mutants but also identified 4 mutants of additional oemiR outer envelope loci. Altogether our study revealed a role of the outer envelope to tolerate cold conditions and showcasts the power of the oemiR collection to research the significance of outer envelope proteins.
Present, empathetic, and persuaded: a meta-analytic comparison of storytelling in high versus low immersive mediated environments
Authors: Ma Zexin , Ma Rong , Chen Meng , Walter Nathan
Published: August 2023

Immersive narratives—narratives viewed in immersive mediated environments—are a promising tool for increasing empathy and persuasion due to their presumed capacity to place viewers inside a story world. Empirical studies, however, have produced mixed findings. This meta-analysis synthesized findings on the effects of narratives viewed in high (vs. low) immersive environments on empathy and persuasion (k = 25). It also examined the impact of narratives viewed in high (vs. low) immersive environments on presence and narrative transportation, psychological constructs associated with two key mechanisms identified in immersive narrative research. Results showed that narratives viewed in high (vs. low) immersive environments had small positive effects on empathy and persuasion. The effect of immersion level on presence was significant, positive, and strong, but the effect on transportation was not significant, perhaps due to the limited sample size (k = 4). This study contributes to further understanding the potential of immersive narratives.
Structure of multidisciplinary heart teams, a survey-based heart team study
Authors: Imran Hamid Umar , Modine Thomas , Maessen Jos , van ‘t Hof Arnoud , Sondergaard Lars , Bleiziffer Sabine , Lancellotti Patrizio , Siepe Matthias , Sardari Nia Peyman
Published: August 2023

OBJECTIVES

Multidisciplinary approach is well established in various disciplines, with evidence highlighting improved patient outcomes. The objective of this survey was to determine the real-world practice of heart teams across Europe.

METHODS

The survey was drafted after a consensus opinion from the authors. The survey was sent to cardiac surgeons and cardiologists identified through electronic search. The survey link and the information sheet were sent through email followed by survey completion reminders. The survey responses were cumulated and analysed.

RESULTS

Among 2188 invited clinicians, 220 clinicians from 26 countries took part in the survey (response rate 10%). The completion rate for the survey questions was 85%. A total of 140 (64%) were cardiac surgeons and 80 (36%) were cardiologists. The heart team meeting frequency was weekly according to 104 (55%) respondents. This was conducted face to face according to 139 (73%) of the responses. Eighty-seven (56%) of the respondents reported 10–20% of patients undergoing percutaneous coronary intervention were discussed at the heart team meeting. Seventy-nine (47%) respondents had ad hoc percutaneous coronary intervention institutional guidelines. Fifty-four (32%) respondents reported an audit process for the heart team decisions.

CONCLUSIONS

This survey suggests that there is marked variability in the infra-structure and execution of heart teams in different institutions. The results of the survey suggest a need to formulate guidelines on the composition and execution of heart teams which may result in an increase in transparency of decision-making within different institutions in reporting and comparing outcomes.
A second-order bulk–surface splitting for parabolic problems with dynamic boundary conditions
Authors: Altmann Robert , Zimmer Christoph
Published: August 2023

This paper introduces a novel approach for the construction of bulk–surface splitting schemes for semilinear parabolic partial differential equations with dynamic boundary conditions. The proposed construction is based on a reformulation of the system as a partial differential–algebraic equation and the inclusion of certain delay terms for the decoupling. To obtain a fully discrete scheme, the splitting approach is combined with finite elements in space and a backward differentiation formula in time. Within this paper, we focus on the second-order case, resulting in a $3$-step scheme. We prove second-order convergence under the assumption of a weak CFL-type condition and confirm the theoretical findings by numerical experiments. Moreover, we illustrate the potential for higher-order splitting schemes numerically.
Race and gender intertwined: why intersecting identities matter for perceptions of incivility and content moderation on social media
Authors: Hawkins Ian , Roden Jessica , Attal Miriam , Aqel Haleemah
Published: August 2023

Social media users often push back against harmful rhetoric with satirical and aggressive counterspeech. How do the interconnected race and gender identities of the person posting counterspeech and the person viewing it impact evaluations of the comment? Across two online experiments, we manipulate the race (Black or White) and gender (man or woman) of an individual whose tweet opposes ignorance about White privilege to examine if identity influences perceptions of incivility and intentions to flag the tweet for removal among Black and White men and women participants. Results demonstrate White men were most likely to find the tweet uncivil and report it, and this was especially the case when the tweet came from a Black woman, regardless of the tone. These studies highlight the importance of recognizing power and intersectionality in social media content moderation and creating policies that counteract the uniquely severe treatment of Black women by White men.
Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network
Authors: Wattier Rachel L , Bucayu Robert F T , Boge Craig L K , Ross Rachael K , Yildirim Inci , Zaoutis Theoklis E , Palazzi Debra L , Vora Surabhi B , Castagnola Elio , Avilés-Robles Martha , Danziger-Isakov Lara , Tribble Alison C , Sharma Tanvi S , Arrieta Antonio C , Maron Gabriela , Berman David M , Yin Dwight E , Sung Lillian , Green Michael , Roilides Emmanuel , Belani Kiran , Romero José , Soler-Palacin Pere , López-Medina Eduardo , Nolt Dawn , Bin Hussain Ibrahim Zaid , Muller William J , Hauger Sarmistha B , Halasa Natasha , Dulek Daniel , Pong Alice , Gonzalez Blanca E , Abzug Mark J , Carlesse Fabianne , Huppler Anna R , Rajan Sujatha , Aftandilian Catherine , Ardura Monica I , Chakrabarti Arunaloke , Hanisch Benjamin , Salvatore Christine M , Klingspor Lena , Knackstedt Elizabeth D , Lutsar Irja , Santolaya Maria E , Shuster Sydney , Johnson Sarah K , Steinbach William J , Fisher Brian T
Published: August 2023

Background

Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown.

Methods

Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression.

Results

In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51–3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51–3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%).

Conclusions

Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.
Multimission view of the low-luminosity ‘obscured’ phase of GRS 1915+105
Authors: Athulya M P , Nandi Anuj
Published: August 2023

GRS 1915+105 has been observed in an ‘obscured’ phase since 2019 May, exhibiting steady and low X-ray luminosities with sporadic re-brightenings. In this paper, we perform a comprehensive and wide-band analysis of the spectral and timing properties of the source during the period 2019–2021 using observations from AstroSat (SXT: 0.5–8 keV; LAXPC: 3–60 keV), the Neutron star Interior Composition Explorer (NICER) (0.5–12 keV), and the Nuclear Spectroscopic Telescope Array (NuSTAR) (3–60 keV). Spectral analysis reveals the presence of a highly variable obscurer ($N_{\rm H_{\rm 1}}\sim$ 1022–1024 atoms cm−2) throughout the observation period. The source is detected in the low/hard state for most of the time, with the spectra being described by a Comptonized component (Γ ∼ 1.16–1.79, kTe ∼ 2–31 keV). The source spectra steepen (Γ ∼ 2.5), indicating a softening of the spectrum, during the rise of the re-brightenings. Various emission and absorption lines corresponding to the neutral Fe Kα, Fe xxv Kα, Fe xxvi Kα, and the Ni xxviii Kα were detected, with the equivalent widths varying in the range 70 eV–3.5 keV. The column density of the absorbing plasma varied in the range 1016–1018 atoms cm−2 at a distance ≤2 × 1010 cm. Interestingly, the source is also seen to exhibit various variability classes (ρ, λ, δ, χ) at relatively low luminosities (∼0.01 LEdd) during the re-brightening phases. Different variability classes show the signature of quasi-periodic oscillations (νQPO: 20–180 mHz, rmsQPO: 7.5  per cent–16  per cent). The source showed a maximum bolometric luminosity (Lbol) of ∼0.01 LEdd (re-brightening phases) and a minimum Lbol of 0.004 LEdd (quiet phase) during the period. We discuss the possible disc dynamics around the black hole during this low-luminosity ‘obscured’ phase.
Four additional natural 7-deazaguanine derivatives in phages and how to make them
Authors: Cui Liang , Balamkundu Seetharamsing , Liu Chuan-Fa , Ye Hong , Hourihan Jacob , Rausch Astrid , Hauß Christopher , Nilsson Emelie , Hoetzinger Matthias , Holmfeldt Karin , Zhang Weijia , Martinez-Alvarez Laura , Peng Xu , Tremblay Denise , Moineau Sylvain , Solonenko Natalie , Sullivan Matthew B , Lee Yan-Jiun , Mulholland Andrew , Weigele Peter R , de Crécy-Lagard Valérie , Dedon Peter C , Hutinet Geoffrey
Published: August 2023

Bacteriophages and bacteria are engaged in a constant arms race, continually evolving new molecular tools to survive one another. To protect their genomic DNA from restriction enzymes, the most common bacterial defence systems, double-stranded DNA phages have evolved complex modifications that affect all four bases. This study focuses on modifications at position 7 of guanines. Eight derivatives of 7-deazaguanines were identified, including four previously unknown ones: 2′-deoxy-7-(methylamino)methyl-7-deazaguanine (mdPreQ1), 2′-deoxy-7-(formylamino)methyl-7-deazaguanine (fdPreQ1), 2′-deoxy-7-deazaguanine (dDG) and 2′-deoxy-7-carboxy-7-deazaguanine (dCDG). These modifications are inserted in DNA by a guanine transglycosylase named DpdA. Three subfamilies of DpdA had been previously characterized: bDpdA, DpdA1, and DpdA2. Two additional subfamilies were identified in this work: DpdA3, which allows for complete replacement of the guanines, and DpdA4, which is specific to archaeal viruses. Transglycosylases have now been identified in all phages and viruses carrying 7-deazaguanine modifications, indicating that the insertion of these modifications is a post-replication event. Three enzymes were predicted to be involved in the biosynthesis of these newly identified DNA modifications: 7-carboxy-7-deazaguanine decarboxylase (DpdL), dPreQ1 formyltransferase (DpdN) and dPreQ1 methyltransferase (DpdM), which was experimentally validated and harbors a unique fold not previously observed for nucleic acid methylases.
What Is Cumulative Cultural Evolution?
Authors: Caldwell Christine A.
Published: August 2023

Within the field of cultural evolution, particular attention has been devoted to the process of cumulative cultural evolution (CCE). Much of modern human behaviour is believed to be attributable to CCE. Despite common consensus over the importance of this topic, there are disparities in how the term has been defined and interpreted (and correspondingly the breadth of phenomena it is considered to encompass). Defined broadly, CCE refers to processes of cultural change involving alterations in cultural traits occurring over multiple episodes of social transmission, but there is variation in the additional criteria considered to be defining features. This chapter will highlight points of contention by examining some key borderline cases, which illustrate how the preferred definition of CCE impacts its presumed scope (e.g. whether it is restricted to humans). It is likely that differing motivations for interest in CCE underpin some of the differences in characterization of the process.
Cultural Evolution and Population Health Interventions
Authors: Alvergne Alexandra
Published: August 2023

Culture is often invoked as an explanation for disparities in health or as a barrier to success in population health interventions, yet the micro-level processes underpinning cultural inertia and cultural epidemics are rarely unpacked. By contrast, a cultural evolution framework breaks down ‘culture’ as a population of cultural variants and focuses on uncovering the social learning ‘strategies’ and individual motivations leading to behavioural variation and change. This chapter elaborates on how thinking evolutionarily can help understand the bi-directional relationship between behaviour and culture, thereby shedding light on the processes leading to the adoption, transmission, and maintenance of behaviour over time and across socio-ecological contexts. The chapter begins by introducing the concept of culture in epidemiology as well as contemporary evolutionary approaches to culture. It then considers how a cultural evolution framework can be deployed at various levels of interventions, from health-message framing and norms-based messaging to social network and communities-based interventions. Lastly, it offers an evaluation of how a cultural evolution framework can be harnessed to tackle public health challenges, including how to seed new healthy behaviour, how to spread behaviour beyond its initial uptake, and how to maintain behaviour in the face of changing ecologies. While cultural evolution (CE) studies of population health (PH) issues are currently limited, there is a large scope for CE and PH to mutually benefit from joining forces.
Autoantibodies against the melanoma differentiation–associated protein 5 in patients with dermatomyositis target the helicase domains
Authors: Van Gompel Eveline , Demirdal Deniz , Fernandes-Cerqueira Catia , Horuluoglu Begum , Galindo-Feria Angeles , Wigren Edvard , Gräslund Susanne , De Langhe Ellen , Benveniste Olivier , Notarnicola Antonella , Chemin Karine , Lundberg Ingrid E
Published: August 2023

Objectives

Clinical observations in patients with dermatomyositis (DM) and autoantibodies against the melanoma differentiation–associated protein 5 (MDA5) suggest that the autoantibodies contribute to the pathogenesis of MDA5(+) DM. To gain insight into the role of the anti-MDA5 autoantibodies, we aimed to identify their binding sites on the different domains of the MDA5 protein.

Methods

We developed an in-house ELISA to assess the reactivity against the MDA5 domains (conformational epitopes) in plasma (n = 8) and serum (n = 24) samples from MDA5(+) patients with varying clinical manifestations and disease outcomes. The reactivities were also assessed using western blot (linearized epitopes). An ELISA-based depletion assay was developed to assess cross-reactivity among the different MDA5 domains.

Results

All eight plasma samples consistently showed reactivity towards conformational and linearized epitopes on the helicase domains of the MDA5 protein. The ELISA-based depletion assay suggests that anti-MDA5 autoantibodies specifically target each of the three helicase domains. Twenty-two of the 24 serum samples showed reactivity in the in-house ELISA and all 22 displayed reactivity towards the helicase domains of the MDA5 protein.

Conclusions

Our data revealed that the main immunogenic targets of anti-MDA5 autoantibodies from MDA5(+) patients are the helicase domains. Considering that the helicase domains are responsible for the enzymatic activity and subsequent triggering of an inflammatory response, our findings suggest that binding of anti-MDA5 autoantibodies could alter the canonical activity of the MDA5 protein and potentially affect the downstream induction of a pro-inflammatory cascade.
Pathogenetic associations of anti-ribosomal P protein antibody titres and their subclasses in patients with systemic lupus erythematosus
Authors: Kaneko Yoshikatsu , Sato Hiroe , Wakamatsu Ayako , Kobayashi Daisuke , Sato Kaho , Kurosawa Yoichi , Hasegawa Eriko , Nakatsue Takeshi , Kuroda Takeshi , Narita Ichiei
Published: August 2023

Objectives

We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese SLE patients.

Methods

Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. The anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA.

Results

Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index was correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed that the anti-RibP index was independently associated with the initial prednisolone dose and the prevalence of skin rash. The anti-RibP IgGs were mainly the IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher DAS, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity.

Conclusion

Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE.
Genetic architecture of well-being: cumulative effect of serotonergic polymorphisms
Authors: Fan Yuhe , Yang Yuting , Shi Lele , Zhao Wenping , Kong Feng , Gong Pingyuan
Published: August 2023

Serotonin influences mental health and well-being. To understand the influences of genetic variations in serotonin pathway on well-being, we examined the effects of seven serotonergic polymorphisms on subjective well-being (i.e. affective balance and global life satisfaction) and psychological well-being (i.e. optimal psychological functions in the face of existential challenges) in a larger sample. Results indicated that the cumulative genetic score, but single genetic effects of serotonergic polymorphisms, was related to individual differences in well-being. Specifically, individuals with a greater cumulative genetic score, which is related to a low risk of depression, tended to exhibit high levels of subjective well-being and psychological well-being. These findings suggest that the overall serotoninergic genetic profile, rather than a specific genetic polymorphism, could greatly influence the individual differences in well-being.
For-Profit Businesses as Public Health Partners to Promote COVID-19 Vaccination
Authors: McHugh Megan , Harris Alexandra , Maechling Claude R. , Holl Jane L.
Published: August 2023

Objective

This study aimed to describe the actions used by health professionals employed by large, for-profit businesses to promote uptake of COVID-19 vaccines, and factors that facilitated and hindered coordination with local public health leaders.

Methods

In this qualitative multiple case study, we conducted telephone interviews with health professionals from businesses, health department leaders, and others who could provide information about local vaccination efforts (e.g., emergency managers, reporters).

Results

Businesses' self-interest (i.e., need to keep employees working), vaccine mandates, and characteristics of the businesses (e.g., ownership, expertise) facilitated leadership in COVID-19 vaccination efforts. Coordination with local health departments was influenced by the resources of the local health department and history of collaboration.

Conclusions

Health professionals employed by large businesses can serve as key public health partners, but their role is shaped by characteristics of the businesses and communities.
Evaluation of the efficacy of tongue swab and saliva as samples for testing COVID-19 infection in symptomatic cases in comparison with nasopharyngeal swab
Authors: Jacob Anjali Anne , C.C. Cleetus , Mohan Girija , Mathew Renu , Matteethra George Chandy , M. Afferedi , B. Manju M. , David Alice
Published: August 2023

Introduction. COVID-19 caused by SARS CoV-2 continues to be a major health concern globally. Methods for detection of the disease are necessary for public health efforts to monitor the spread of this disease as well as for detecting the emergence of new variants.

Gap statement. Collection of Nasopharyngeal swab (NPS), the gold standard sample for the detection of COVID-19 infection by RT-qPCR is invasive and requires the expertise of a trained medical provider. This highlights the need for validating less invasive samples that can be self-collected without the need for trained medical provider.

Aim. To validate saliva and tongue swab as potential samples for the diagnosis of COVID-19.

Methodology. Adult and paediatric cases who had acute influenza like illness were enrolled in the study. The study involved comparison of Nucleic Acid Amplification Tests (NAAT) results for the detection of COVID-19 obtained by using saliva and tongue swab with that of NPS.

Result and Conclusion. The sensitivity and specificity of saliva as sample for COVID-19 detection were found to be 71 and 88% respectively whereas those of tongue swab as sample were 78 and 90 %. Further validation was based on the positive and negative predictive values, the likelihood ratio, agreement percentage and the kappa statistic. The findings of the study point towards tongue swab and saliva as suitable alternative samples for the diagnosis of COVID-19 with a slightly higher accuracy and agreement for tongue swab than saliva. However considering the fatality of COVID-19, they are better suited for mass screening of people than for diagnosis.
Stiffness anisotropy coordinates supracellular contractility driving long-range myotube-ECM alignment
Authors: Skillin Nathaniel P. , Kirkpatrick Bruce E. , Herbert Katie M. , Nelson Benjamin R. , Hach Grace K. , Günay Kemal Arda , Khan Ryan M. , DelRio Frank W. , White Timothy J. , Anseth Kristi S.
Published: August 2023

In skeletal muscle tissue, injury-related changes in stiffness activate muscle stem cells through mechanosensitive signaling pathways. Functional muscle tissue regeneration also requires the effective coordination of myoblast proliferation, migration, polarization, differentiation, and fusion across multiple length scales. Here, we demonstrate that substrate stiffness anisotropy coordinates contractility-driven collective cellular dynamics resulting in C2C12 myotube alignment over millimeter-scale distances. When cultured on mechanicallyanisotropicliquid crystalline polymer networks (LCNs) lacking topographic features that could confer contact guidance, C2C12 myoblasts collectively polarize in the stiffest direction of the substrate. Cellular coordination is amplified through reciprocal cell-ECM dynamics that emerge during fusion, driving global myotube-ECM ordering. Conversely, myotube alignment was restricted to small local domains with no directional preference on mechanicallyisotropicLCNs of same chemical formulation. These findings reveal a role for stiffness anisotropy in coordinating emergent collective cellular dynamics, with implications for understanding skeletal muscle tissue development and regeneration.
Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents
Authors: Compte Joan , Tible Marion , Cuadros Thais , Romero-Gimenez Jordi , Laguna Ariadna , Aubry Jean-François , Dumont Erik , Constans Charlotte , Tiennot Thomas , Santin Mathieu D. , Lehericy Stephane , Vila Miquel
Published: August 2023

Age-dependent accumulation of the brain pigment neuromelanin has been implicated in the pathogenesis of Parkinson’s disease (PD). In humans, intracellular and extracellular neuromelanin levels are increased in PD postmortem brains and boosting neuromelanin production in rodents compromises neuronal function and viability and triggers a PD-like phenotype. Focused ultrasound has been shown to reduce ultraviolet light-induced skin hyperpigmentation in guinea pig and to remove brain extracellular β-amyloid plaques in Alzheimer’s mouse models. Here we show that repeated application of transcranial focused ultrasound (tFUS) is able to decrease intracellular and extracellular neuromelanin levels in neuromelanin-producing parkinsonian rats, compared to sham-treated animals, without the need for any additional therapeutic agent or intervention. Reduced neuromelanin levels in tFUS-treated animals were associated with decreased Lewy-like pathology, preserved dopaminergic phenotype, attenuated nigrostriatal degeneration, reduced glial activation, and long-term recovery of motor function. Our findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage. This FDA-approved technology should thus be explored further as a noninvasive method with neuroprotective potential in PD and to maintain neuromelanin to levels below its pathogenic threshold within the aging population.

One Sentence Summary

Transcranial focused ultrasound reduces age-dependent neuromelanin accumulation and provides therapeutic benefit in parkinsonian rats
Crohn’s patients and healthy infants share immunodominant B cell response to commensal flagellin peptide epitopes
Authors: Zhao Qing , Duck Lennard Wayne , Killian John T. , Rosenberg Alexander F. , Mannon Peter J. , Glenn King R. , Denson Lee A. , Kugathasan Subra , Janoff Edward N. , Jenmalm Maria C. , Elson Charles O.
Published: August 2023

About half of patients with Crohn’s disease (CD) develop selective serum IgG response to flagellin proteins of theLachnospiraceaefamily. Here, we identified a dominant B cell peptide epitope in CD, locating in the highly conserved “hinge region” between the D0 and D1 domains at the amino-terminus ofLachnospiraceaeflagellins. Serum IgG reactive to this epitope is present at an elevated level in adult CD patients and in pediatric CD patients at diagnosis. Most importantly, high levels of serum IgG to the hinge epitope were found in most infants from 3 different geographic regions (Uganda, Sweden, and the USA) at one year of age. This vigorous homeostatic response decrements with age as it is not present in healthy adults. These data identify a distinct subset of CD patients, united by a shared reactivity to this dominant flagellin epitope that may represent failure of a homeostatic response beginning in infancy.
A cortico-subcortical loop for motor control via the pontine reticular formation
Authors: Bősz Emília , Plattner Viktor M. , Biró László , Kóta Kata , Diana Marco A. , Acsády László
Published: August 2023

Movement and locomotion are controlled by large neuronal circuits like the cortex-basal ganglia (BG)-thalamus loop. Inhibitory output of the BG loop can directly control movement via specialized connections with the brainstem. Whether other parallel loops with similar logic exist is presently unclear. Here we demonstrate that glycine transporter 2-positive (GlyT2+) cells of the pontine reticular formation (PRF) receive cortical inputs and in turn innervate the thalamus. Thalamus-projecting GlyT2+ cells innervate subcortical regions distinct from BG targets. Cortical cells co-innervate PRF/GlyT2+ cells and thalamus as in the BG loops. Cortex exerts strong excitatory control on PRF/GlyT2+ cells and these neurons powerfully inhibit their thalamic targets. Activation of thalamus projecting PRF/GlyT2+ cells leads to contralateral turning. These results demonstrate that the PRF is part of a cortico-subcortical loop that regulates motor activity parallel to the BG circuits. The cortico-PRF-thalamus loop can synergistically control turning with the BG loops via distinct descending pathways.

Graphical abstract
Dietary cystine restriction increases the proliferative capacity of the small intestine of mice
Authors: de Jong Judith C.W. , van Rooijen Kristel S. , Stigter Edwin C.A. , Can Gülersönmez M. , de Zoete Marcel R. , Top Janetta , Baars Matthijs J.D. , Vercoulen Yvonne , Kuipers Folkert , van Mil Saskia W.C. , Ijssennagger Noortje
Published: August 2023

Over 88 million people are currently estimated to have adopted towards a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine concentrations. Sufficient uptake of cysteine is crucial, as it serves as substrate for protein synthesis and conversion to taurine and glutathione. In this study, we therefore investigate the effect of low dietary cystine, the oxidized derivative of cysteine, on intestinal epithelial layer function. Mice (8/group) received a high fat diet with normal or low cystine concentration for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels after 2 weeks. Stem cell markers as well as the proliferation markerKi67were increased upon cystine restriction in the small intestine. In line with this, gene set enrichment analysis indicated enrichment of Wnt signaling in the small intestine of mice on the low cystine diet, indicative of proliferative cells. Increased proliferation was absent in the colon. In the colon, dietary cystine restriction results in an increase in goblet cells, but no significant changes in the thickness of the mucus barrier or in its protective capacity. Also the microbiome was not changed upon dietary restriction. In conclusion, we show that cystine restriction for two weeks does not seem to induce any systemic effects. The increased proliferative capacity and number of goblet cells observed in the intestine may be the effect of starting epithelial damage or a reaction of the epithelium to start enlarging the absorptive capacity.
The RIDD activity ofC. elegansIRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival
Authors: Ying Mingjie , Argon Yair , Gidalevitz Tali
Published: August 2023

Xbp1splicing and regulated IRE1-dependent RNA decay (RIDD) are two RNase activities of the ER stress sensor IRE1. WhileXbp1splicing has important roles in stress responses and animal physiology, the physiological role(s) of RIDD remain enigmatic. Genetic evidence inC. elegansconnects XBP1-independent IRE1 activity to organismal stress adaptation, but whether this is via RIDD, and what are the targets is yet unknown. We show that cytosolic kinase/RNase domain ofC. elegansIRE1 is indeed capable of RIDD in human cells, and that sensory neurons use RIDD to signal environmental stress, by degrading mRNA of TGFβ-like growth factor DAF-7.daf-7was degraded in human cells by both human and worm IRE1 RNAse activity with same efficiency and specificity asBlos1,confirmingdaf-7as RIDD substrate. Surprisingly,daf-7degradationin vivowas triggered by concentrations of ER stressor tunicamycin too low forxbp-1splicing. Decrease in DAF-7 normally signals food limitation and harsh environment, triggering adaptive changes to promote population survival. BecauseC. elegansis a bacteriovore, and tunicamycin, like other common ER stressors, is an antibiotic secreted byStreptomyces spp., we asked whetherdaf-7degradation by RIDD could signal pending food deprivation. Indeed, pre-emptive tunicamycin exposure increased survival ofC. eleganspopulations under food limiting/high temperature stress, and this protection was abrogated by overexpression of DAF-7. Thus,C. elegansuses stress-inducing metabolites in its environment as danger signals, and employs IRE1’s RIDD activity to modulate the neuroendocrine signaling for survival of upcoming environmental challenge.
Target-aware Variational Auto-encoders for Ligand Generation with Multimodal Protein Representation Learning
Authors: Ngo Nhat Khang , Hy Truong Son
Published: August 2023

Without knowledge of specific pockets, generating ligands based on the global structure of a protein target plays a crucial role in drug discovery as it helps reduce the search space for potential drug-like candidates in the pipeline. However, contemporary methods require optimizing tailored networks for each protein, which is arduous and costly. To address this issue, we introduceTargetVAE, a target-aware variational auto-encoder that generates ligands with high binding affinities to arbitrary protein targets, guided by a novel multimodal deep neural network built based on graph Transformers as the prior for the generative model. This is the first effort to unify different representations of proteins (e.g., sequence of amino-acids, 3D structure) into a single model that we name asProtein Multimodal Network(PMN). Our multimodal architecture learns from the entire protein structures and is able to capture their sequential, topological and geometrical information. We showcase the superiority of our approach by conducting extensive experiments and evaluations, including the assessment of generative model quality, ligand generation for unseen targets, docking score computation, and binding affinity prediction. Empirical results demonstrate the promising performance of our proposed approach. Our software package is publicly available athttps://github.com/HySonLab/Ligand_Generation.
The effects of economic difficulties on social and health care costs of children –target trial emulation using complete birth cohort data in Finland
Authors: Hiilamo Aapo , Keski-Säntti Markus , Juutinen Aapo , Mäkinen Lauri , Ristikari Tiina , Lallukka Tea
Published: August 2023

It is unclear how much costs economic difficulties incur to the health and social care sector, which is a critical research gap to support the economic case for preventing child poverty. We examine the health and social service costs due to families entering into, and transitioning out of, social assistance used as a proxy measure for economic difficulties. We analyzed register data on all Finnish children born in 1997 in the framework of a non-randomized target trial. Inverse probability treatment weighting techniques were used to make the comparison group similar to the treatment group in terms of 29 pretreatment variables. Entry to social assistance was associated with some 1398-2591€ (50%) higher cumulative health and social care costs of the children three years after their families transitioned to social assistance, compared to the group that did not enter to social assistance system. This difference was primarily attributed to higher social care costs. Continued social assistance use was associated with some 1018-2775€ (31%) higher costs compared to the comparison group that exited social assistance. These findings support an economic argument to prevent families from entering economic difficulties and to help those in such situations to transition out.
Unraveling the link between Neuropathy Target Esterase NTE/SWS, lysosomal storage diseases, inflammation, and abnormal fatty acid metabolism
Authors: Tsap Mariana I. , Yatsenko Andriy S. , Hegermann Jan , Beckmann Bibiana , Tsikas Dimitrios , Shcherbata Halyna R.
Published: August 2023

Mutations inDrosophilaSwiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that SWS is present in surface glia that form the blood-brain-barrier (BBB) and that SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression ofDrosophilaSWS or human NTE in theswsmutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly,swsmutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Since a defective BBB is associated with many neurodegenerative diseases, a better understanding of the molecular mechanisms of inflammation may help to promote the use of anti-inflammatory therapy for age-related neurodegeneration.
AePUbpromoter length modulates gene expression inAedes aegypti
Authors: Anderson Michelle A.E. , Leftwich Philip T. , Wilson Ray , Carabajal Paladino Leonela Z. , Basu Sanjay , Rooney Sara , Adelman Zach N. , Alphey Luke
Published: August 2023

Molecular tools for modulating transgene expression inAedes aegyptiare few. Here we demonstrate that adjustments to theAePUbpromoter length can alter expression levels of two reporter proteins inAe. aegypticell culture and in mosquitoes. This provides a simple means for increasing or decreasing expression of a gene of interest and easy translation from cells to whole insects.
Short oligomers rather than rings of human RAD52 promote single-strand annealing
Authors: Kharlamova Maria A. , Kushwah Manish S. , Jachowski Tobias J. , Subramaniam Sivaraman , Stewart A. Francis , Kukura Philipp , Schäffer Erik
Published: August 2023

Genome maintenance and stability rely on the repair of DNA double-strand breaks. The break repair can be mediated by the single-strand annealing protein RAD52. RAD52 forms rings that are thought to promote annealing. However, RAD52’s annealing activity decreases with increasing concentrations that favor ring formation. Thus, which oligomeric form and how RAD52 anneals DNA strands and detects sequence homology is unclear. We combine mass photometry with biochemical assays to quantify oligomeric states of human RAD52 with and without DNA and put forward an alternative mechanism illustrating the critical role of short oligomers for single-stranded DNA annealing. We found that while truncated RAD52 formed undecameric rings at nanomolar concentrations, full-length RAD52 was mostly monomeric at lower nanomolar, physiological concentrations. At higher concentrations, it formed rings with a variable stoichiometry from heptamers to tridecamers. At low concentrations, with hardly any rings present, RAD52 already promoted single-strand annealing. Rings and short oligomers could bind at least two single DNA strands, but if complementary strands were both bound to rings annealing was inhibited. Our findings suggest that single-strand annealing and homology detection is mediated by short oligomers of RAD52 instead of rings.