bluuebunny/crossref_metadata_2025 huggingface dataset:
Donne transgender nello sport: è solo un problema di valori di testosterone?
Authors: Garofalo Vincenzo , Calogero Aldo E.
Published: February 2023

Sommario

Il Comitato Olimpico Internazionale (CIO) consente alle atlete transgender di gareggiare nelle divisioni femminili se i loro livelli di testosterone sierico sono inferiori a 10 nmol/L dal almeno un anno. Tuttavia, questo valore è nettamente superiore rispetto alle donne cisgender. Gli elevati livelli di testosterone e i loro effetti fisiologici determinano un vantaggio nelle competizioni sportive. La terapia ormonale di affermazione di genere riduce i livelli di testosterone circolante e determina alcune variazioni nella fisiologia del testosterone nelle donne transgender con conseguente modifica delle prestazioni fisiche di queste atlete. Scopo di questa Rassegna è la valutazione dei cambiamenti indotti dalla terapia ormonale e l’analisi degli effetti irreversibili del testosterone e di come essi possano influire sulle capacità fisiche e atletiche di donne transgender, con lo scopo finale di rendere lo sport inclusivo ed equo per tutti gli atleti.
Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy
Authors: Zhang Qingfei , Kuang Gaizhen , Li Wenzhao , Wang Jinglin , Ren Haozhen , Zhao Yuanjin
Published: February 2023

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects. Currently, the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy. For this purpose, stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection, prolonged blood circulation, specific tumor accumulation, and controlled release profile of nucleic acid drugs. Besides, synergistic therapy could be achieved when combined with other therapeutic regimens. This review summarizes recent advances in various stimuli-responsive nanocarriers for gene delivery. Particularly, the nanocarriers responding to endogenous stimuli including pH, reactive oxygen species, glutathione, and enzyme, etc., and exogenous stimuli including light, thermo, ultrasound, magnetic field, etc., are introduced. Finally, the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed. The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.
First Confirmed Record of the Smalltooth Sand Tiger, Odontapis Ferox, in Galicia (NW Spain)
Authors: Mucientes Gonzalo , Vilas-Arrondo Nair , Secci-Petretto Giulia , Vázquez Uxía , Pin Xabier , López Alfredo , Castro L. Filipe C. , Froufe Elsa
Published: February 2023

The smalltooth sand tiger shark Odontaspis ferox (Risso, 1810) appears to have an extensive and fragmented distribution in tropical and warm-temperate worldwide oceans. One female of O. ferox was caught and released by a small-scale fishery vessel in Ría de Arousa (Northwest of Spain), subsequently stranded still alive on the coast (42°33’18.4"N 8°49’18.3"O) after a few hours. The individual (336 cm total length, weight ~ 300 kg) was identified based on a collection of features including the characteristic dentition, body morphology and by molecular assignment. This is the first confirmed record of O. ferox in Galician waters. This finding complements the knowledge of the geographic distribution and occurrence of this rare and sparse species in the Northeastern Atlantic.
Are Confident Parents Really Aware of Children’s Online Risks? A Conceptual Model and Validation of Parental Self-Efficacy, Mediation, and Awareness Scales
Authors: Kuldas Seffetullah , Sargioti Aikaterini , Staksrud Elisabeth , Heaney Darran , Norman James O’Higgins
Published: February 2023

Children’s use of the Internet comes with both risks and opportunities. To minimize risks and maximize opportunities, parents may choose to observe, enable, and/or restrict their children’s Internet use. However, parents’ high confidence in their children’s online safety can itself be a risk factor inhibiting parental awareness of online risks. This research aims to test whether confident parents are accurately aware of how frequently their child has experienced risks online. To this end, construct validity and reliability of scales measuring parental self-efficacy, restrictive-enabling-observant mediation, awareness, and Internet use were established first. Next, a conceptual model of parental awareness was proposed. These results were based on a two-parameter-logistic-model of item response theory, minimum-rank factor analysis, and parallel-mediation analysis of self-reports by a convenience sample of 388 parents in Ireland (Autumn 2019). Confident parents mostly reported their child experienced no online risk in the past couple of months, whereas unconfident parents reported their child experienced an online risk once, twice, or more times. Results of the mediation analysis indicated that confident parents likely underestimated, whereas unconfident parents overestimated, how frequently their child experienced an online risk. The accuracy of parental awareness depended on their mediation strategies, particularly restrictive mediation. Further research is needed to test whether training parents on self-efficacy and mediation of children’s Internet use raises their awareness of the children’s online risks.
YoNet: A Neural Network for Yoga Pose Classification
Authors: Ashraf Faisal Bin , Islam Muhammad Usama , Kabir Md Rayhan , Uddin Jasim
Published: February 2023

Yoga has become an integral part of human life to maintain a healthy body and mind in recent times. With the growing, fast-paced life and work from home, it has become difficult for people to invest time in the gymnasium for exercises. Instead, they like to do assisted exercises at home where pose recognition techniques play the most vital role. Recognition of different poses is challenging due to proper dataset and classification architecture. In this work, we have proposed a deep learning-based model to identify five different yoga poses from comparatively fewer amounts of data. We have compared our model’s performance with some state-of-the-art image classification models-ResNet, InceptionNet, InceptionResNet, Xception and found our architecture superior. Our proposed architecture extracts spatial, and depth features from the image individually and considers them for further calculation in classification. The experimental results show that it achieved 94.91% accuracy with 95.61% precision.
Different responses of agroecosystem greenhouse gas emissions to tillage practices in a Chinese wheat–maize cropping system
Authors: Li Zhaoxin , Zhang Qiuying , Li Zhao , Qiao Yunfeng , Du Kun , Yue Zewei , Tian Chao , Leng Peifang , Cheng Hefa , Chen Gang , Li Fadong
Published: February 2023

To mitigate greenhouse gas (GHG) emissions of intensified agriculture, conservation practices are gradually being implemented in Chinese wheat–maize cropping systems. However, the effects of different tillage practices on agricultural field GHG emissions and subsequent global warming potential (GWP) are poorly documented. In this study, a three-year field experiment was conducted from 2019 to 2021 to assess the effects of tillage on the emissions of carbon dioxide (CO2), methane (CH4), nitrous oxide (N2O), and eventually GWP. Compared to conventional tillage (CT), no-tillage (NT) significantly decreased CO2, CH4, and N2O emissions by 35.43%, 67.33%, 339.07%, respectively, which resulted in a decrease of 37.25% in GWP during three annual cycles. Based on the results of this study, soil could potentially act as a net source of CO2 and CH4 under both CT and NT, and a net sink of N2O under NT. Annually, non-growing season contributed 16.9%, 15.6%, and 13.8% soil CO2, CH4, and N2O fluxes, and 16.6% GWP under CT and 17.3%, 16.4%, 21.6%, and 17.3% under NT, respectively. Compared to CT, NT improved the aboveground biomass and grain yields of wheat by 21.3% and 13.3% from averaged results, respectively; no significant differences were found for maize yields. Although principal component analysis showed that soil temperature had higher correlations with CO2 emissions and GWP as compared to soil moisture, soil moisture affected GHG emissions more than soil temperature as demonstrated by the structural equation model. The modeling analysis found that NT increased soil moisture, pH, and bulk density, thus increasing soil organic carbon and decreasing total nitrogen content, eventually inhibiting GHG emissions. This research demonstrated that NT had the potential to mitigate GHG emissions, yet stability needed further investigation on long-term scales.∙

Graphical Abstract
Effects of rotor separation on the axial descent performance of dual-rotor configurations
Authors: Veismann Marcel , Dougherty Christopher , Gharib Morteza
Published: February 2023

Rotorcraft can encounter highly unsteady flow when descending at a steep angle, leading to a flow condition called vortex ring state, which is associated with strong oscillatory airloads and substantial losses in mean rotor thrust. This study examines the aerodynamic coupling between closely arranged rotors in vertical flight and assesses the extent to which rotor–rotor interactions affect the rotor performance in this flight stage. Wind tunnel experiments were performed on a small-scale, dual-rotor set-up with adjustable rotor spacing, and the effect of rotor separation on thrust generation was quantified. Pairs of 4 in., 5 in. and 6 in. rotors (

$3.0 \times 10^4< Re<8.1 \times 10^4$

) were investigated, with load cell measurements showing significant thrust losses and concomitantly increased thrust oscillations as descent rate increased. Peak losses and fluctuations were consistently recorded at descent rates of 1.2–1.3 times the hover induced velocity for all rotor sizes and separations. While tests showed that the mean aerodynamic performance of dual-rotor systems is generally similar to that of single rotors, appreciable changes to the descent characteristics could be observed at low rotor separations. Particle image velocimetry flow visualization suggests considerable changes to the flow field as rotor separation decreases, where individual vortex ring systems merge into a single vortex ring structure.
Association between a priori and a posteriori dietary patterns and the risk of type 2 diabetes: a representative cohort study in Taiwan
Authors: Lin Rong , Chien Kuo-Liong , Tsai Ming-Chieh , Wang Yi-Jie , Hsu Le-Yin
Published: February 2023

The present study aimed to investigate the relationship between dietary patterns and the risk of type 2 diabetes mellitus (T2DM) among Taiwanese individuals. Data were collected using a nationwide cohort study (2001–15) from the Triple-High Database. Dietary intake was assessed using the twenty-group food frequency questionnaire and used to calculate alternate Mediterranean diet (aMED) and Dietary Approaches to Stop Hypertension (DASH) scores. Principal component analysis (PCA) and partial least-squares (PLS) regression were used to derive dietary patterns, with incident T2DM as the outcome. Multivariable-adjusted hazard ratios and 95 % confidence intervals were calculated using time-dependent Cox proportional hazards (Cox PH) regression analysis, and subgroup analyses were performed. A total of 4705 participants were enrolled in the study, and 995 had newly developed T2DM during the median 5⋅28-year follow-up period (30⋅7 per 1000 person-years). Six dietary patterns were extracted (PCA: Western, prudent, dairy and plant-based; PLS: health-conscious, fish-vegetable and fruit-seafood). The highest aMED score quartile had a 25 % (hazard ratio 0⋅75; 95 % CI 0⋅61, 0⋅92; P = 0⋅039) lower risk of T2DM than the lowest quartile. This association remained significant after adjustment (adjusted hazard ratio 0⋅74; 95 % CI 0⋅60, 0⋅91; P = 0⋅010), and no effect modifier was found for aMED. The DASH scores, PCA and PLS dietary patterns were not significant after adjustment. In conclusion, high adherence to a MED-type dietary pattern by Taiwanese foods was associated with a lower risk of T2DM in the Taiwanese population, regardless of unhealthy lifestyle habits.
Mendelian randomization as a tool to inform drug development using human genetics
Authors: Daghlas Iyas , Gill Dipender
Published: February 2023

Drug development is essential to the advancement of human health, however, the process is slow, costly, and at high risk of failure at all stages. A promising strategy for expediting and improving the probability of success in the drug development process is the use of naturally randomized human genetic variation for drug target identification and validation. These data can be harnessed using the Mendelian randomization (MR) analytic paradigm to proxy the lifelong consequences of genetic perturbations of drug targets. In this review, we discuss the myriad applications of the MR paradigm for human drug target identification and validation. We review the methodology and applications of MR, key limitations of MR, and potential future opportunities for research. Throughout the review, we refer to illustrative examples of MR analyses investigating the consequences of genetic inhibition of interleukin 6 signaling which, in some cases, have anticipated results from randomized controlled trials. As human genetic data become more widely available, we predict that MR will serve as a key pillar of support for drug development efforts.
The role of telephone clinics in ENT
Authors: Brimioulle M , Arih I , Pervaiz A , Patel W , Davies A , Sekyi-Djan M , Qureishi A , Chaidas K
Published: February 2023

Objective

This quality improvement project assessed the outcomes of telephone consultations for ENT patients in order to identify areas where telephone consultations may be useful in the long term.

Method

New ENT patient appointments in May 2019 and May 2020 were reviewed. Total outcomes as well as subspecialty-specific and presentation-specific outcomes were compared for telephone versus face-to-face consultations.

Results

There were 638 consultations in total (465 in 2019 and 173 in 2020). Following telephone consultations, more patients were followed up and fewer patients were listed for surgery or discharged. Overall outcomes for subspecialties followed the general trend, albeit with a few variations.

Conclusion

Lack of clinical examination in telephone consultations likely affects confidence in making a diagnosis and therefore discharging or listing patients for surgery. Nevertheless, looking at specialty-specific and presentation-specific data, there may be a role for telephone consultations in selected patients.
A computational neuroimaging study of reinforcement learning and goal-directed exploration in schizophrenia spectrum disorders
Authors: Culbreth A. J. , Schwartz E. K. , Frank M. J. , Brown E. C. , Xu Z. , Chen S. , Gold J. M. , Waltz J. A.
Published: February 2023

Background

Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level.

Methods

We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data.

Results

Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function.

Conclusions

These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers.
Nominal Compounds in Old English Meter and Prosody
Authors: Minkova Donka , Zhou Z.L.
Published: February 2023

What is the lexicon’s role in licensing the selection of phonologically-marked structures in Old English verse? Specifically, what is its role in the avoidance of certain nominal compounds in verse, even though the same compounds are used apparently freely in prose (Terasawa 1994)? Using a simulation of the Old English lexicon, we offer a statistical analysis of the poetic use of nominal compounds compared to the availability of relevant prosodic structures in the ambient language. In the process, we unify Terasawa’s separate constraints and demonstrate a new way of addressing the complex interplay between Old English prosody and the structure of Old English alliterative meter. Our results endorse Terasawa’s position: We find that the dispreference for nominal compounds of the XX-LX type is a general but noncategorical property of Old English. We attribute their highly restricted usage in verse to the demands of poetic diction and their incompatibility with the metrical templates that scops and scribes replicate. Additionally, while syllable weight factors into metrical organization, it does so less for stress placement, which remains morphologically grounded; this asymmetry in the ranking value of weight between poetry and prose is considered briefly in the context of the Old English monastic scribal training.
An Artistic Product of Globalised Singapore? The Damaru Pan-Indian Folk Drumming Ensemble
Authors: LAI JINXING (GENE)
Published: February 2023

Damaru is a Singaporean Indian folk drumming ensemble that promotes pan-Indian identity and Indian folk drumming in the city-state. This article examines how Damaru navigates and carves a niche in Singapore’s multicultural milieu with the concept of a pan-Indian folk drumming ensemble, and how drummers create artistic products that engage an audience of different sociocultural backgrounds. An analysis of two of Damaru’s rhythmic compositions suggests that drumming, mixing Indian folk drums and rhythmic patterns, and performing the rhythmic patterns in sequence have helped Damaru’s rhythmic compositions reach a broader audience, enabling the ensemble to win state grants and performance opportunities.
Exploring the Meteorological Impacts of Surface and Rooftop Heat Mitigation Strategies Over a Tropical City
Authors: Khan Ansar , Khorat Samiran , Doan Quang‐Van , Khatun Rupali , Das Debashish , Hamdi Rafiq , Carlosena Laura , Santamouris Mattheos , Georgescu Matei , Niyogi Dev
Published: February 2023

Different heat mitigation technologies have been developed to improve the thermal environment in cities. However, the regional impacts of such technologies, especially in the context of a tropical city, remain unclear. The deployment of heat mitigation technologies at city‐scale can change the radiation balance, advective flow, and energy balance between urban areas and the overlying atmosphere. We used the mesoscale Weather Research and Forecasting model coupled with a physically based single‐layer urban canopy model to assess the impacts of five different heat mitigation technologies on surface energy balance, standard surface meteorological fields, and planetary boundary layer (PBL) dynamics for premonsoon typical hot summer days over a tropical coastal city in the month of April in 2018, 2019, and 2020. Results indicate that the regional impacts of cool materials (CMs), super‐cool broadband radiative coolers, green roofs (GRs), vegetation fraction change, and a combination of CMs and GRs (i.e., “Cool city (CC)”) on the lower atmosphere are different at diurnal scale. Results showed that super‐cool materials have the maximum potential of ambient temperature reduction of 1.6°C during peak hour (14:00 LT) compared to other technologies in the study. During the daytime hours, the PBL height was considerably lower than the reference scenario with no implementation of strategies by 700 m for super‐cool materials and 500 m for both CMs and CC cases; however, the green roofing system underwent nominal changes over the urban area. During the nighttime hours, the PBL height increased by CMs and the CC strategies compared to the reference scenario, but minimal changes were evident for super‐cool materials. The changes of temperature on the vertical profile of the heat mitigation implemented city reveal a stable PBL over the urban domain and a reduction of the vertical mixing associated with a pollution dome. This would lead to crossover phenomena above the PBL due to the decrease in vertical wind speed. Therefore, assessing the coupled regional impact of urban heat mitigation over the lower atmosphere at city‐scale is urgent for sustainable urban planning.
Rare and Revealing: Radiocarbon in Service of Paleoceanography
Authors: Skinner Luke , Bard Edouard
Published: February 2023

While radiocarbon is best known as a dating tool, this rare isotope can also provide unique and wide-ranging insights into the cycling of carbon in the Earth system.
Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain
Authors: Chen Chao , Sun Linlin , Adler Avital , Zhou Hang , Zhang Licheng , Zhang Lihai , Deng Junhao , Bai Yang , Zhang Jinhui , Yang Guang , Gan Wen-Biao , Tang Peifu
Published: February 2023

Increased low frequency cortical oscillations are observed in people with neuropathic pain, but the cause of such elevated cortical oscillations and their impact on pain development remain unclear. By imaging neuronal activity in a spared nerve injury (SNI) mouse model of neuropathic pain, we show that neurons in dorsal root ganglia (DRG) and somatosensory cortex (S1) exhibit synchronized activity after peripheral nerve injury. Notably, synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations. This DRG synchrony is initiated by axotomized neurons and mediated by local purinergic signaling at the site of nerve injury. We further show that synchronized DRG activity after SNI is responsible for increasing low frequency cortical oscillations and synaptic remodeling in S1, as well as for inducing animals’ pain-like behaviors. In naive mice, enhancing the synchrony, not the level, of DRG neuronal activity causes synaptic changes in S1 and pain-like behaviors similar to SNI mice. Taken together, these results reveal the critical role of synchronized DRG neuronal activity in increasing cortical plasticity and oscillations in a neuropathic pain model. These findings also suggest the potential importance of detection and suppression of elevated cortical oscillations in neuropathic pain states.
Electrically controlled superconductor-to-failed insulator transition and giant anomalous Hall effect in kagome metal CsV3Sb5 nanoflakes
Authors: Zheng Guolin , Tan Cheng , Chen Zheng , Wang Maoyuan , Zhu Xiangde , Albarakati Sultan , Algarni Meri , Partridge James , Farrar Lawrence , Zhou Jianhui , Ning Wei , Tian Mingliang , Fuhrer Michael S. , Wang Lan
Published: February 2023

The electronic correlations (e.g. unconventional superconductivity (SC), chiral charge order and nematic order) and giant anomalous Hall effect (AHE) in topological kagome metals AV3Sb5 (A = K, Rb, and Cs) have attracted great interest. Electrical control of those correlated electronic states and AHE allows us to resolve their own nature and origin and to discover new quantum phenomena. Here, we show that electrically controlled proton intercalation has significant impacts on striking quantum phenomena in CsV3Sb5 nanodevices mainly through inducing disorders in thinner nanoflakes and carrier density modulation in thicker ones. Specifically, in disordered thin nanoflakes (below 25 nm), we achieve a quantum phase transition from a superconductor to a “failed insulator” with a large saturated sheet resistance for T → 0 K. Meanwhile, the carrier density modulation in thicker nanoflakes shifts the Fermi level across the charge density wave (CDW) gap and gives rise to an extrinsic-intrinsic transition of AHE. With the first-principles calculations, the extrinsic skew scattering of holes in the nearly flat bands with finite Berry curvature by multiple impurities would account for the giant AHE. Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition (SIT), outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV3Sb5 family.
Future therapies for cystic fibrosis
Authors: Allen Lucy , Allen Lorna , Carr Siobhan B. , Davies Gwyneth , Downey Damian , Egan Marie , Forton Julian T. , Gray Robert , Haworth Charles , Horsley Alexander , Smyth Alan R. , Southern Kevin W. , Davies Jane C.
Published: February 2023

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.
A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis
Authors: He Yibo , Ge Changrong , Moreno-Giró Àlex , Xu Bingze , Beusch Christian M. , Sandor Katalin , Su Jie , Cheng Lei , Lönnblom Erik , Lundqvist Christina , Slot Linda M. , Tong Dongmei , Urbonaviciute Vilma , Liang Bibo , Li Taotao , Lahore Gonzalo Fernandez , Aoun Mike , Malmström Vivianne , Rispens Theo , Ernfors Patrik , Svensson Camilla I. , Scherer Hans Ulrich , Toes René E. M. , Gjertsson Inger , Ekwall Olov , Zubarev Roman A. , Holmdahl Rikard
Published: February 2023

Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certain RA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer
Authors: Hong Lingzhi , Aminu Muhammad , Li Shenduo , Lu Xuetao , Petranovic Milena , Saad Maliazurina B. , Chen Pingjun , Qin Kang , Varghese Susan , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Spelman Amy , Elamin Yasir Y. , Negrao Marcelo V. , Skoulidis Ferdinandos , Gay Carl M. , Cascone Tina , Gandhi Saumil J. , Lin Steven H. , Lee Percy P. , Carter Brett W. , Wu Carol C. , Antonoff Mara B. , Sepesi Boris , Lewis Jeff , Gibbons Don L. , Vaporciyan Ara A. , Le Xiuning , Jack Lee J. , Roy-Chowdhuri Sinchita , Routbort Mark J. , Gainor Justin F. , Heymach John V. , Lou Yanyan , Wu Jia , Zhang Jianjun , Vokes Natalie I.
Published: February 2023

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), andSTK11andJAK2alterations as features associate with a higher likelihood of early progression on ICI-mono.CDKN2Aalterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.
Quantifying the direct and indirect protection provided by insecticide treated bed nets against malaria
Authors: Unwin H. Juliette T. , Sherrard-Smith Ellie , Churcher Thomas S. , Ghani Azra C.
Published: February 2023

Long lasting insecticidal nets (LLINs) provide both direct and indirect protection against malaria. As pyrethroid resistance evolves in mosquito vectors, it will be useful to understand how the specific benefits LLINs afford individuals and communities may be affected. Here we use modelling to show that there is no minimum LLIN usage needed for users and non-users to benefit from community protection. Modelling results also indicate that pyrethroid resistance in local mosquitoes will likely diminish the direct and indirect benefits from insecticides, leaving the barrier effects intact, but LLINs are still expected to provide enhanced benefit over untreated nets even at high levels of pyrethroid resistance.
Gut microbiota-mediated secondary bile acid alleviates Staphylococcus aureus-induced mastitis through the TGR5-cAMP-PKA-NF-κB/NLRP3 pathways in mice
Authors: Zhao Caijun , Wu Keyi , Hao Haoyang , Zhao Yihong , Bao Lijuan , Qiu Min , He Yuhong , He Zhaoqi , Zhang Naisheng , Hu Xiaoyu , Fu Yunhe
Published: February 2023

Although emerging evidence shows that gut microbiota-mediated metabolic changes regulate intestinal pathogen invasions, little is known about whether and how gut microbiota-mediated metabolites affect pathogen infection in the distal organs. In this study, untargeted metabolomics was performed to identify the metabolic changes in a subacute ruminal acidosis (SARA)-associated mastitis model, a mastitis model with increased susceptibility toStaphylococcus aureus(S. aureus). The results showed that cows with SARA had reduced cholic acid (CA) and deoxycholic acid (DCA) levels compared to healthy cows. Treatment of mice with DCA, but not CA, alleviatedS. aureus-induced mastitis by improving inflammation and the blood-milk barrier integrity in mice. DCA inhibited the activation of NF-κB and NLRP3 signatures caused byS. aureusin the mouse mammary epithelial cells, which was involved in the activation of TGR5. DCA-mediated TGR5 activation inhibited the NF-κB and NLRP3 pathways and mastitis caused byS. aureusvia activating cAMP and PKA. Moreover, gut-dysbiotic mice had impaired TGR5 activation and aggravatedS. aureus-induced mastitis, while restoring TGR5 activation by spore-forming bacteria reversed these changes. Furthermore, supplementation of mice with secondary bile acids producerClostridium scindensalso activated TGR5 and alleviatedS. aureus-induced mastitis in mice. These results suggest that impaired secondary bile acid production by gut dysbiosis facilitates the development ofS. aureus-induced mastitis and highlight a potential strategy for the intervention of distal infection by regulating gut microbial metabolism.
Surface nanoengineering technology for the removal of sulfur compounds associated with negative attributes in wines
Authors: Mierczynska-Vasilev Agnieszka M. , Kulcsar Allie C. , Dabare Panthihage Ruvini L. , Vasilev Krasimir A. , Bekker Marlize Z.
Published: February 2023

Volatile sulfur compounds (VSCs), such as hydrogen sulfide, methanethiol, and ethanethiol, are associated with ‘reductive’ aromas in wine and contribute to approximately 30% of all wine faults. These compounds can have a significant impact on wine aroma and perceived quality, and subsequently, consumer preference. In this communication, we report a method for the removal of VSC compounds based on nanoengineered surfaces that incorporate immobilized gold nanoparticles.
Distilling experience into a physically interpretable recommender system for computational model selection
Authors: Huang Xinyi , Chyczewski Thomas , Xia Zhenhua , Kunz Robert , Yang Xiang
Published: February 2023

Model selection is a chronic issue in computational science. The conventional approach relies heavily on human experience. However, gaining experience takes years and is severely inefficient. To address this issue, we distill human experience into a recommender system. A trained recommender system tells whether a computational model does well or poorly in handling a physical process. It also tells if a physical process is important for a quantity of interest. By accumulating this knowledge, the system is able to make recommendations about computational models. We showcase the power of the system by considering Reynolds-averaged-Navier–Stokes (RANS) model selection in the field of computational fluid dynamics (CFD). Since turbulence is stochastic, there is no universal RANS model, and RANS model selection has always been an issue. A working model recommending system saves fluid engineers years and allows junior CFD practitioners to make sensible model choices like senior ones.
Reactive oxygen metabolism in the proliferation of Korean pine embryogenic callus cells promoted by exogenous GSH
Authors: Gao Fang , Wang Ruirui , Shi Yujie , Shen Hailong , Yang Ling
Published: February 2023

Exogenous glutathione (GSH) promotes the proliferation of embryogenic callus (EC) cells in Korean pine in the course of somatic embryogenesis, and reactive oxygen species (ROS) may play an important role in regulating the proliferation of EC cells by exogenous GSH. However, the concrete metabolic response of ROS is unclear. In this study, two cell lines of Korean pine with high proliferative potential 001#-001 (F, Fast proliferative potential cell line is abbreviated as F) and low proliferative potential 001#-010 (S, Slow proliferative potential cell line is abbreviated as S) were used as test materials. The responses of ROS-related enzymes and substances to exogenous GSH and L-Buthionine-sulfoximine (BSO) were investigated in EC cells. The results showed that the exogenous addition of GSH increased the number of early somatic embryogenesis (SEs) in EC cells of both F and S cell lines, decreased the amount of cell death in both cell lines. Exogenous addition of GSH promoted cell division in both cell lines, increased intracellular superoxide dismutase (SOD) and catalase (CAT) activities, inhibited intracellular hydrogen peroxide (H2O2), malondialdehyde (MDA) and nitric oxide (NO) production, and increased NO/ROS ratio. In conclusion, the exogenous GSH promoting the proliferation of Korean pine EC cells, the activity of intracellular antioxidant enzymes was enhanced, the ROS level was reduced, and the resistance of cells to stress was enhanced.
The role of tumor model in magnetic targeting of magnetosomes and ultramagnetic liposomes
Authors: Curcio Alberto , Perez Jose Efrain , Prévéral Sandra , Fromain Alexandre , Genevois Coralie , Michel Aude , Van de Walle Aurore , Lalatonne Yoann , Faivre Damien , Ménager Christine , Wilhelm Claire
Published: February 2023

The combined passive and active targeting of tumoral tissue remains an active and relevant cancer research field. Here, we exploit the properties of two highly magnetic nanomaterials, magnetosomes and ultramagnetic liposomes, in order to magnetically target prostate adenocarcinoma tumors, implanted orthotopically or subcutaneously, to take into account the role of tumor vascularization in the targeting efficiency. Analysis of organ biodistribution in vivo revealed that, for all conditions, both nanomaterials accumulate mostly in the liver and spleen, with an overall low tumor retention. However, both nanomaterials were more readily identified in orthotopic tumors, reflecting their higher tumor vascularization. Additionally, a 2- and 3-fold increase in nanomaterial accumulation was achieved with magnetic targeting. In summary, ultramagnetic nanomaterials show promise mostly in the targeting of highly-vascularized orthotopic murine tumor models.
Targeting BAP1 with small compound inhibitor for colon cancer treatment
Authors: Kang Minhwa , Park Seul Gi , Lee Shin-Ai , Kim Soyi , Lee Daye , Shirbhate Mukesh Eknath , Youn So-Yeon , Kim Kwan Mook , Cha Sun-Shin , Kwon Jongbum
Published: February 2023

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 μM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.
Multi-centre deep learning for placenta segmentation in obstetric ultrasound with multi-observer and cross-country generalization
Authors: Andreasen Lisbeth Anita , Feragen Aasa , Christensen Anders Nymark , Thybo Jonathan Kistrup , Svendsen Morten Bo S. , Zepf Kilian , Lekadir Karim , Tolsgaard Martin Grønnebæk
Published: February 2023

The placenta is crucial to fetal well-being and it plays a significant role in the pathogenesis of hypertensive pregnancy disorders. Moreover, a timely diagnosis of placenta previa may save lives. Ultrasound is the primary imaging modality in pregnancy, but high-quality imaging depends on the access to equipment and staff, which is not possible in all settings. Convolutional neural networks may help standardize the acquisition of images for fetal diagnostics. Our aim was to develop a deep learning based model for classification and segmentation of the placenta in ultrasound images. We trained a model based on manual annotations of 7,500 ultrasound images to identify and segment the placenta. The model's performance was compared to annotations made by 25 clinicians (experts, trainees, midwives). The overall image classification accuracy was 81%. The average intersection over union score (IoU) reached 0.78. The model’s accuracy was lower than experts’ and trainees’, but it outperformed all clinicians at delineating the placenta, IoU = 0.75 vs 0.69, 0.66, 0.59. The model was cross validated on 100 2nd trimester images from Barcelona, yielding an accuracy of 76%, IoU 0.68. In conclusion, we developed a model for automatic classification and segmentation of the placenta with consistent performance across different patient populations. It may be used for automated detection of placenta previa and enable future deep learning research in placental dysfunction.
Accountable survival contrast-learning for optimal dynamic treatment regimes
Authors: Choi Taehwa , Lee Hyunjun , Choi Sangbum
Published: February 2023

Dynamic treatment regime (DTR) is an emerging paradigm in recent medical studies, which searches a series of decision rules to assign optimal treatments to each patient by taking into account individual features such as genetic, environmental, and social factors. Although there is a large and growing literature on statistical methods to estimate optimal treatment regimes, most methodologies focused on complete data. In this article, we propose an accountable contrast-learning algorithm for optimal dynamic treatment regime with survival endpoints. Our estimating procedure is originated from a doubly-robust weighted classification scheme, which is a model-based contrast-learning method that directly characterizes the interaction terms between predictors and treatments without main effects. To reflect the censorship, we adopt the pseudo-value approach that replaces survival quantities with pseudo-observations for the time-to-event outcome. Unlike many existing approaches, mostly based on complicated outcome regression modeling or inverse-probability weighting schemes, the pseudo-value approach greatly simplifies the estimating procedure for optimal treatment regime by allowing investigators to conveniently apply standard machine learning techniques to censored survival data without losing much efficiency. We further explore a SCAD-penalization to find informative clinical variables and modified algorithms to handle multiple treatment options by searching upper and lower bounds of the objective function. We demonstrate the utility of our proposal via extensive simulations and application to AIDS data.
Familiarity, age, weaning and health status impact social proximity networks in dairy calves
Authors: Vázquez-Diosdado Jorge A. , Occhiuto Francesca , Carslake Charles , Kaler Jasmeet
Published: February 2023

Social network analysis in dairy calves has not been widely studied, with previous studies limited by the short study duration, and low number of animals and replicates. In this study, we investigated social proximity interactions of 79 Holstein–Friesian calves from 5 cohorts for up to 76 days. Networks were computed using 4-day aggregated associations obtained from ultrawideband location sensor technology, at 1 Hz sampling rate. The effect of age, familiarity, health, and weaning status on the social proximity networks of dairy calves was assessed. Networks were poorly correlated (non-stable) between the different 4-day periods, in the majority of them calves associated heterogeneously, and individuals assorted based on previous familiarity for the whole duration of the study. Age significantly increased association strength, social time and eigenvector centrality and significantly decreased closeness and coefficient of variation in association (CV). Sick calves had a significantly lower strength, social time, centrality and CV, and significantly higher closeness compared to the healthy calves. During and after weaning, calves had significantly lower closeness and CV, and significantly higher association strength, social time, and eigenvector centrality. These results indicate that age, familiarity, weaning, and sickness have a significant impact on the variation of social proximity interaction of calves.
A novel task of canine olfaction for use in adult and senior pet dogs
Authors: Khan Michael Z. , Mondino Alejandra , Russell Katharine , Case Beth , Fefer Gilad , Woods Hope , Olby Natasha , Gruen Margaret
Published: February 2023

While much work has been done in the field of canine olfaction, there has been little exploration of hyposmia or anosmia. This is partly due to difficulties in reducing confounds like training history and environmental distraction. The current study describes a novel olfaction test using spontaneous search behavior in dogs to find a hidden food treat in a three-choice task with both light-phase and dark-phase conditions. The study was performed in 18 adult control dogs, 18 senior/geriatric dogs enrolled in a longitudinal aging study, and a single dog with severe nasal pathology. In the senior/geriatric and control groups, dogs performed with higher accuracy (p < 0.0001) and were less likely to show biased selection strategy (p < 0.01) in the dark-phase than light-phase. While senior/geriatric dogs performed above chance, they had lower accuracy in the dark-phase compared to controls (p = 0.036). Dogs who scored higher on an owner questionnaire of cognitive decline showed a positive correlation with performance in the dark-phase; performance on additional cognitive tests did not correlate with performance in the dark-phase. This task can be used to quantify canine olfaction using clearly defined endpoints and spontaneous behaviors thus making it feasible to compare between and within groups of pet dogs.