bluuebunny/crossref_metadata_2025 huggingface dataset:
Receding resilience: On the planetary moods of disruption
Authors: Grove Nicole Sunday
Published: November 2022

The term disruption has been offered as both an ethos and set of practices framed as a broad response to all manner of social and political ills. This article offers a speculative reflection on disruption as a planetary mood, and the sensory qualities of a change in politics no longer defined by governance and what is governable, but by a series of continuous experiments hedged upon the creation of new geopolitical frontiers and life forms that position all matter and contingency towards a specific kind of value tied to chaos. In thinking about the kinds of authority and legitimacy being fashioned around visions of so-called disruptive futures, I draw on materially-grounded illustrations of disruptive dispositions to examine three different arrangements of affect, feeling, and intensity being animated to give disruption its power of transmissibility and adaptability, as well as its unintuitive emphasis on disorder and ‘breaking things’ as both a moral good and unconditional response to questions concerning global conflict, crises, and instability. Ultimately, disruption as a planetary mood draws on a libidinal economy that does not bend towards justice or equity, thus warning against misanthropic commitments to collapse and the consequences of investing in a world premised on an ethos of erasure.
Yogurt consumption and risk of mortality from all causes, CVD and cancer: a comprehensive systematic review and dose–response meta-analysis of cohort studies
Authors: Tutunchi Helda , Naghshi Sina , Naemi Mohammad , Naeini Fatemeh , Esmaillzadeh Ahmad
Published: November 2022

Objectives:

To quantify the dose–response relation between yogurt consumption and risk of mortality from all causes, CVD and cancer.

Design:

Systematic review and meta-analysis.

Setting:

We conducted a comprehensive search of PubMed/Medline, ISI Web of Science and Scopus databases through August 2022 for cohort studies reporting the association of yogurt consumption with mortality from all causes, CVD and cancer. Summary relative risks (RR) and 95 % CI were calculated with a random-effects model.

Participants:

Seventeen cohort studies (eighteen publications) of 896 871 participants with 75 791 deaths (14 623 from CVD and 20 554 from cancer).

Results:

High intake of yogurt compared with low intake was significantly associated with a lower risk of deaths from all causes (pooled RR 0·93; 95 % CI: 0·89, 0·98, I2 = 47·3 %, n 12 studies) and CVD (0·89; 95 % CI: 0·81, 0·98, I2 = 33·2 %, n 11), but not with cancer (0·96; 95 % CI: 0·89, 1·03, I2 = 26·5 %, n 12). Each additional serving of yogurt consumption per d was significantly associated with a reduced risk of all-cause (0·93; 95 % CI: 0·86, 0·99, I2 = 63·3 %, n 11) and CVD mortality (0·86; 95 % CI: 0·77, 0·99, I2 = 36·6 %, n 10). There was evidence of non-linearity between yogurt consumption and risk of all-cause and CVD mortality, and there was no further reduction in risk above 0·5 serving/d.

Conclusion:

Summarising earlier cohort studies, we found an inverse association between yogurt consumption and risk of all-cause and CVD mortality; however, there was no significant association between yogurt consumption and risk of cancer mortality.
Exploring differences between public and private providers in primary care: findings from a large Swedish region
Authors: Glenngård Anna Häger
Published: November 2022

This study contributes to the sparse literature on differences between public and private primary care practices (PCCs). The purpose was to explore if differences in performance and characteristics between public and PCCs persist over time in a welfare market with patient choice and provider competition, where public and private providers operate under similar conditions. The analysis is based on data from a national patient survey and administrative registries in a large Swedish region, covering PCC observations in 2010 and 2019, i.e., the year after and 10 years after introducing choice and competition in the region. The findings suggest that differences across owner types tend to decrease over time in welfare markets. Differences in patients' experiences, PCC size, patient mix and the division of labour have decreased or disappeared between 2010 and 2019. There were small but significant differences in process measures of quality in 2019; public PCCs complied better with prescription guidelines. While the results demonstrate a convergence between public and private PCCs in regards to their characteristics and performance, differences in patients' experiences in regards to socioeconomic conditions persisted. Such unwarranted variation calls for continued attention from policy makers and further research about causes.
Inter‐Model Spread of the Simulated Winter Surface Air Temperature Over the Eurasian Continent and the Physical Linkage to the Jet Streams From the CMIP6 Models
Authors: Liu Anqi , Huang Ying , Huang Danqing
Published: November 2022

The model uncertainty, one of the major sources of projection uncertainty, is still a challenge in the climate simulation. In this study, we investigated the inter‐model spread of the simulated winter surface air temperature (SAT) over the Eurasian continent and the physical link to the upper‐level jet streams from the Coupled Model Inter‐comparison Project Phase 6 models. Extracted by the inter‐model empirical orthogonal function analysis, the leading inter‐model spread of SAT over the Eurasian continent is characterized by a cold pattern, particularly over high latitudes, which is closely associated with the out‐of‐phase variation in the intensity of the East Asian polar front jet (EAPJ) and East Asian subtropical jet (EASJ). The weakened‐EAPJ‐enhanced‐EASJ pattern is linked to the intensified Siberian high, the strengthened Aleutian low, and the deepened East Asian trough. All the variations would benefit the cold air invasion, resulting in the leading inter‐model spread of the SAT. The possible mechanism for the inter‐model uncertainty in the out‐of‐phase variation in the intensity of the two jets would be traced to the cooling over the Northwest Pacific oceans, which has reduced (enhanced) the meridional temperature gradient over high (low) latitudes and thereby contributed to the out of phase variation in the two jets. Our findings would help provide a potential metric for understanding the winter SAT change over the Eurasian continent.
mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma
Authors: Xu Wendan , Berning Philipp , Erdmann Tabea , Grau Michael , Bettazová Nardjas , Zapukhlyak Myroslav , Frontzek Fabian , Kosnopfel Corinna , Lenz Peter , Grondine Michael , Willis Brandon , Lynch James T. , Klener Pavel , Hailfinger Stephan , Barry Simon T. , Lenz Georg
Published: November 2022

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell–like (ABC) and germinal center B-cell–like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
Predicting criminal and violent outcomes in psychiatry: a meta-analysis of diagnostic accuracy
Authors: Watts Devon , de Azevedo Cardoso Taiane , Librenza-Garcia Diego , Ballester Pedro , Passos Ives Cavalcante , Kessler Felix H. P. , Reilly Jim , Chaimowitz Gary , Kapczinski Flavio
Published: November 2022

Although reducing criminal outcomes in individuals with mental illness have long been a priority for governments worldwide, there is still a lack of objective and highly accurate tools that can predict these events at an individual level. Predictive machine learning models may provide a unique opportunity to identify those at the highest risk of criminal activity and facilitate personalized rehabilitation strategies. Therefore, this systematic review and meta-analysis aims to describe the diagnostic accuracy of studies using machine learning techniques to predict criminal and violent outcomes in psychiatry. We performed meta-analyses using the mada, meta, and dmetatools packages in R to predict criminal and violent outcomes in psychiatric patients (n = 2428) (Registration Number: CRD42019127169) by searching PubMed, Scopus, and Web of Science for articles published in any language up to April 2022. Twenty studies were included in the systematic review. Overall, studies used single-nucleotide polymorphisms, text analysis, psychometric scales, hospital records, and resting-state regional cerebral blood flow to build predictive models. Of the studies described in the systematic review, nine were included in the present meta-analysis. The area under the curve (AUC) for predicting violent and criminal outcomes in psychiatry was 0.816 (95% Confidence Interval (CI): 70.57–88.15), with a partial AUC of 0.773, and average sensitivity of 73.33% (95% CI: 64.09–79.63), and average specificity of 72.90% (95% CI: 63.98–79.66), respectively. Furthermore, the pooled accuracy across models was 71.45% (95% CI: 60.88–83.86), with a tau squared (τ2) of 0.0424 (95% CI: 0.0184–0.1553). Based on available evidence, we suggest that prospective models include evidence-based risk factors identified in prior actuarial models. Moreover, there is a need for a greater emphasis on identifying biological features and incorporating novel variables which have not been explored in prior literature. Furthermore, available models remain preliminary, and prospective validation with independent datasets, and across cultures, will be required prior to clinical implementation. Nonetheless, predictive machine learning models hold promise in providing clinicians and researchers with actionable tools to improve how we prevent, detect, or intervene in relevant crime and violent-related outcomes in psychiatry.
Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution
Authors: Sodir Nicole M. , Pellegrinet Luca , Kortlever Roderik M. , Campos Tania , Kwon Yong-Won , Kim Shinseog , Garcia Daniel , Perfetto Alessandra , Anastasiou Panayiotis , Swigart Lamorna Brown , Arends Mark J. , Littlewood Trevor D. , Evan Gerard I.
Published: November 2022

Germ-line hypomorphism of the pleiotropic transcription factor Myc in mice, either through Myc gene haploinsufficiency or deletion of Myc enhancers, delays onset of various cancers while mice remain viable and exhibit only relatively mild pathologies. Using a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will, we asked whether this resistance to tumour progression is also emplaced when Myc hypomorphism is acutely imposed in adult mice. Indeed, adult Myc hypomorphism profoundly blocked KRasG12D-driven lung and pancreatic cancers, arresting their evolution at the early transition from indolent pre-tumour to invasive cancer. We show that such arrest is due to the incapacity of hypomorphic levels of Myc to drive release of signals that instruct the microenvironmental remodelling necessary to support invasive cancer. The cancer protection afforded by long-term adult imposition of Myc hypomorphism is accompanied by only mild collateral side effects, principally in haematopoiesis, but even these are circumvented if Myc hypomorphism is imposed metronomically whereas potent cancer protection is retained.
Giant gate-controlled odd-parity magnetoresistance in one-dimensional channels with a magnetic proximity effect
Authors: Takiguchi Kosuke , Anh Le Duc , Chiba Takahiro , Shiratani Harunori , Fukuzawa Ryota , Takahashi Takuji , Tanaka Masaaki
Published: November 2022

According to Onsager’s principle, electrical resistance R of general conductors behaves as an even function of external magnetic field B. Only in special circumstances, which involve time reversal symmetry (TRS) broken by ferromagnetism, the odd component of R against B is observed. This unusual phenomenon, called odd-parity magnetoresistance (OMR), was hitherto subtle (< 2%) and hard to control by external means. Here, we report a giant OMR as large as 27% in edge transport channels of an InAs quantum well, which is magnetized by a proximity effect from an underlying ferromagnetic semiconductor (Ga,Fe)Sb layer. Combining experimental results and theoretical analysis using the linearized Boltzmann’s equation, we found that simultaneous breaking of both the TRS by the magnetic proximity effect (MPE) and spatial inversion symmetry (SIS) in the one-dimensional (1D) InAs edge channels is the origin of this giant OMR. We also demonstrated the ability to turn on and off the OMR using electrical gating of either TRS or SIS in the edge channels. These findings provide a deep insight into the 1D semiconducting system with a strong magnetic coupling.
A formal validation of a deep learning-based automated workflow for the interpretation of the echocardiogram
Authors: Tromp Jasper , Bauer David , Claggett Brian L. , Frost Matthew , Iversen Mathias Bøtcher , Prasad Narayana , Petrie Mark C. , Larson Martin G. , Ezekowitz Justin A. , Solomon Scott D.
Published: November 2022

This study compares a deep learning interpretation of 23 echocardiographic parameters—including cardiac volumes, ejection fraction, and Doppler measurements—with three repeated measurements by core lab sonographers. The primary outcome metric, the individual equivalence coefficient (IEC), compares the disagreement between deep learning and human readers relative to the disagreement among human readers. The pre-determined non-inferiority criterion is 0.25 for the upper bound of the 95% confidence interval. Among 602 anonymised echocardiographic studies from 600 people (421 with heart failure, 179 controls, 69% women), the point estimates of IEC are all <0 and the upper bound of the 95% confidence intervals below 0.25, indicating that the disagreement between the deep learning and human measures is lower than the disagreement among three core lab readers. These results highlight the potential of deep learning algorithms to improve efficiency and reduce the costs of echocardiography.
An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
Authors: Zhang Guohui , Xu Xianjin , Jia Zhiguang , Geng Yanyan , Liang Hongwu , Shi Jingyi , Marras Martina , Abella Carlota , Magleby Karl L. , Silva Jonathan R. , Chen Jianhan , Zou Xiaoqin , Cui Jianmin
Published: November 2022

BK type Ca2+-activated K+channels activate in response to both voltage and Ca2+. The membrane-spanning voltage sensor domain (VSD) activation and Ca2+binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca2+binding to pore opening  are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca2+dependent activation mechanism. BC5 activates the channel in the absence of Ca2+binding but Ca2+binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca2+binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca2+dependent activation and is an important site for allosteric agonists to modulate BK channel activation.
Mechanically derived short-range order and its impact on the multi-principal-element alloys
Authors: Seol Jae Bok , Ko Won-Seok , Sohn Seok Su , Na Min Young , Chang Hye Jung , Heo Yoon-Uk , Kim Jung Gi , Sung Hyokyung , Li Zhiming , Pereloma Elena , Kim Hyoung Seop
Published: November 2022

Chemical short-range order in disordered solid solutions often emerges with specific heat treatments. Unlike thermally activated ordering, mechanically derived short-range order (MSRO) in a multi-principal-element Fe40Mn40Cr10Co10 (at%) alloy originates from tensile deformation at 77 K, and its degree/extent can be tailored by adjusting the loading rates under quasistatic conditions. The mechanical response and multi-length-scale characterisation pointed to the minor contribution of MSRO formation to yield strength, mechanical twinning, and deformation-induced displacive transformation. Scanning and high-resolution transmission electron microscopy and the anlaysis of electron diffraction patterns revealed the microstructural features responsible for MSRO and the dependence of the ordering degree/extent on the applied strain rates. Here, we show that underpinned by molecular dynamics, MSRO in the alloys with low stacking-fault energies forms when loaded at 77 K, and these systems that offer different perspectives on the process of strain-induced ordering transition are driven by crystalline lattice defects (dislocations and stacking faults).
Nanozyme-reinforced hydrogel as a H2O2-driven oxygenerator for enhancing prosthetic interface osseointegration in rheumatoid arthritis therapy
Authors: Zhao Yue , Song Shanliang , Wang Dongdong , Liu He , Zhang Junmin , Li Zuhao , Wang Jincheng , Ren Xiangzhong , Zhao Yanli
Published: November 2022

Stem cell-based therapy has drawn attention for enhancing the osseointegration efficiency after joint replacement in the rheumatoid arthritis (RA). However, therapeutic efficacy of this approach is threatened by the accumulated reactive oxygen species (ROS) and poor oxygen supply. Herein, we develop a nanozyme-reinforced hydrogel for reshaping the hostile RA microenvironment and improving prosthetic interface osseointegration. The engineered hydrogel not only scavenges endogenously over-expressed ROS, but also synergistically produces dissolved oxygen. Such performance enables the hydrogel to be utilized as an injectable delivery vehicle of bone marrow-derived mesenchymal stem cells (BMSCs) to protect implanted cells from ROS and hypoxia-mediated death and osteogenic limitation. This nanozyme-reinforced hydrogel encapsulated with BMSCs can alleviate the symptoms of RA, including suppression of local inflammatory cytokines and improvement of osseointegration. This work provides a strategy for solving the long-lasting challenge of stem cell transplantation and revolutionizes conventional intervention methods for improving prosthetic interface osseointegration in RA.
Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection
Authors: Chen Judy , Deng Jane C. , Zemans Rachel L. , Bahmed Karim , Kosmider Beata , Zhang Min , Peters-Golden Marc , Goldstein Daniel R.
Published: November 2022

Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E2(PGE2), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE2within the aged lung. PGE2impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE2receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.
Immunotherapy in triple negative breast cancer: beyond checkpoint inhibitors
Authors: Abdou Yara , Goudarzi Atta , Yu Jia Xin , Upadhaya Samik , Vincent Benjamin , Carey Lisa A.
Published: November 2022

The development of immunotherapy agents has revolutionized the field of oncology. The only FDA-approved immunotherapeutic approach in breast cancer consists of immune checkpoint inhibitors, yet several novel immune-modulatory strategies are being actively studied and appear promising. Innovative immunotherapeutic strategies are urgently needed in triple negative breast cancer (TNBC), a subtype of breast cancer known for its poor prognosis and its resistance to conventional treatments. TNBC is more primed to respond to immunotherapy given the presence of more tumor infiltrating lymphocytes, higher PD-L1 expression, and higher tumor mutation burden relative to the other breast cancer subtypes, and therefore, immuno-oncology represents a key area of promise for TNBC research. The aim of this review is to highlight current data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches beyond checkpoint inhibitors in TNBC.
Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA
Authors: Haer-Wigman Lonneke , den Ouden Amber , van Genderen Maria M. , Kroes Hester Y. , Verheij Joke , Smailhodzic Dzenita , Hoekstra Attje S. , Vijzelaar Raymon , Blom Jan , Derks Ronny , Tjon-Pon-Fong Menno , Yntema Helger G. , Nelen Marcel R. , Vissers Lisenka E.L.M. , Lugtenberg Dorien , Neveling Kornelia
Published: November 2022

Pathogenic variants in the OPN1LW/OPN1MW gene cluster are causal for a range of mild to severe visual impairments with color deficiencies. The widely utilized short-read next-generation sequencing (NGS) is inappropriate for the analysis of the OPN1LW/OPN1MW gene cluster and many patients with pathogenic variants stay underdiagnosed. A diagnostic genetic assay was developed for the OPN1LW/OPN1MW gene cluster, consisting of copy number analysis via multiplex ligation-dependent probe amplification and sequence analysis via long-read circular consensus sequencing. Performance was determined on 50 clinical samples referred for genetic confirmation of the clinical diagnosis (n = 43) or carrier status analysis (n = 7). A broad range of pathogenic haplotypes were detected, including deletions, hybrid genes, single variants and combinations of variants. The developed genetic assay for the OPN1LW/OPN1MW gene cluster is a diagnostic test that can detect both structural and nucleotide variants with a straightforward analysis, improving diagnostic care of patients with visual impairment.
Sentinel2GlobalLULC: A Sentinel-2 RGB image tile dataset for global land use/cover mapping with deep learning
Authors: Benhammou Yassir , Alcaraz-Segura Domingo , Guirado Emilio , Khaldi Rohaifa , Achchab Boujemâa , Herrera Francisco , Tabik Siham
Published: November 2022

Land-Use and Land-Cover (LULC) mapping is relevant for many applications, from Earth system and climate modelling to territorial and urban planning. Global LULC products are continuously developing as remote sensing data and methods grow. However, there still exists low consistency among LULC products due to low accuracy in some regions and LULC types. Here, we introduce Sentinel2GlobalLULC, a Sentinel-2 RGB image dataset, built from the spatial-temporal consensus of up to 15 global LULC maps available in Google Earth Engine. Sentinel2GlobalLULC v2.1 contains 194877 single-class RGB image tiles organized into 29 LULC classes. Each image is a 224 × 224 pixels tile at 10 × 10 m resolution built as a cloud-free composite from Sentinel-2 images acquired between June 2015 and October 2020. Metadata includes a unique LULC annotation per image, together with level of consensus, reverse geo-referencing, global human modification index, and number of dates used in the composite. Sentinel2GlobalLULC is designed for training deep learning models aiming to build precise and robust global or regional LULC maps.
Mobile resistome of microbial communities and antimicrobial residues from drinking water supply systems in Rio de Janeiro, Brazil
Authors: Bianco Kayo , de Farias Beatriz Oliveira , Gonçalves-Brito Andressa Silva , Alves do Nascimento Ana Paula , Magaldi Mariana , Montenegro Kaylanne , Flores Claudia , Oliveira Samara , Monteiro Mychelle Alves , Spisso Bernardete Ferraz , Pereira Mararlene Ulberg , Ferreira Rosana Gomes , Albano Rodolpho Mattos , Cardoso Alexander Machado , Clementino Maysa Mandetta
Published: November 2022

Antibiotic resistance genes (ARGs) are widespread in the environment due to the overuse of antibiotics and other pollutants, posing a threat to human and animal health. In this study, we evaluated antimicrobial residues, bacterial diversity and ARGs in two important watersheds, Guandu and São João, that supply drinking water to Rio de Janeiro city, Brazil. In addition, tap water samples were collected from three different cities in Rio de Janeiro State, including the metropolitan area of Rio de Janeiro city. Clarithromycin, sulfamethoxazole and azithromycin were found in untreated water and drinking water in all samples. A greater abundance of Proteobacteria was observed in Guandu and São João watersheds, with most of the sequences belonging to the Gammaproteobacteria class. A plasmidome-focused metagenomics approach revealed 4881 (Guandu), 3705 (São João) and 3385 (drinking water) ARGs mainly associated with efflux systems. The genes encoding metallo-β-lactamase enzymes (blaAIM, blaGIM, blaIMP, and blaVIM) were detected in the two watersheds and in drinking water samples. Moreover, we demonstrated the presence of the colistin resistance genes mcr-3 and mcr-4 (both watersheds) and mcr-9 (drinking water and Guandu) for the first time in Brazil. Our data emphasize the importance of introducing measures to reduce the disposal of antibiotics and other pollutants capable of promoting the occurrence and spread of the microbial resistome on aquatic environments and predicting possible negative impacts on human health.
Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1
Authors: Ottenhoff M. J. , Dijkhuizen S. , Ypelaar A. C. H. , de Oude N. L. , Koekkoek S. K. E. , Wang S. S.-H. , De Zeeuw C. I. , Elgersma Y. , Boele H. J.
Published: November 2022

Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1+/− mice to a cerebellum-dependent associative learning task, called Pavlovian eyeblink conditioning. Additionally, we assessed general motor function and muscle strength in Nf1+/− mice. To our surprise, we found that Nf1+/− mice showed a moderately increased learning rate of conditioned eyeblink responses, as well as improved accuracy in the adaptive timing of the eyeblink responses. Locomotion, balance, general motor function, and muscle strength were not affected in Nf1+/− mice. Together, our results support the view that cerebellar function in Nf1+/− mice is unimpaired.
Differentiation of patients with mild cognitive impairment and healthy controls based on computer assisted hand movement analysis: a proof-of-concept study
Authors: Horvath Andras Attila , Berente Dalida Borbala , Vertes Balazs , Farkas David , Csukly Gabor , Werber Tom , Zsuffa Janos Andras , Kiss Mate , Kamondi Anita
Published: November 2022

Mild cognitive impairment (MCI) is the prodromal phase of dementia, and it is highly underdiagnosed in the community. We aimed to develop an automated, rapid (< 5 min), electronic screening tool for the recognition of MCI based on hand movement analysis. Sixty-eight individuals participated in our study, 46 healthy controls and 22 patients with clinically defined MCI. All participants underwent a detailed medical assessment including neuropsychology and brain MRI. Significant differences were found between controls and MCI groups in mouse movement characteristics. Patients showed higher level of entropy for both the left (F = 5.24; p = 0.001) and the right hand (F = 8.46; p < 0.001). Longer time was required in MCI to perform the fine motor task (p < 0.005). Furthermore, we also found significant correlations between mouse movement parameters and neuropsychological test scores. Correlation was the strongest between motor parameters and Clinical Dementia Rating scale (CDR) score (average r: − 0.36, all p’s < 0.001). Importantly, motor parameters were not influenced by age, gender, or anxiety effect (all p’s > 0.05). Our study draws attention to the utility of hand movement analysis, especially to the estimation of entropy in the early recognition of MCI. It also suggests that our system might provide a promising tool for the cognitive screening of large populations.
Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment
Authors: Fontes Magda S. C. , Dingemanse Jasper , Halabi Atef , Tomaszewska-Kiecana Monika , Sidharta Patricia N.
Published: November 2022

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child–Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (Cmax) reached at 4.0 h. There was no difference in Cmax, indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86–1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7–99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required.

Clinical Trial Registration ClinicalTrials.gov NCT04252495.
Mechanical investigations supported by DIC of structural components intended for operation
Authors: Szymczak T. , Brodecki A. , Kowalewski Z. L. , Rudnik D.
Published: November 2022

The paper deals with experimental attempts for determination of the mechanical resistance of various components subjected to static loading by analysis of displacement values in a 3D coordinate system using a non-contact testing method. The problem is studied on the basis of results from tests of the wheelchair and SUV’s wheel, supported by means of a PONTOS 5M Digital Image Correlation (DIC) system enabling determination of the patterns deflection at discretised facet measuring zones of an element. The objects tested extend a knowledge on the components’ behaviour under static loading within their loading capacity. Data collected in the experiments are expressed by variations of the resultant vector of deflection in the 3D coordinate system and images under loading and unloading stages as well. The results enabled to indicate the weakest zone in the wheelchair and to express an influence of the foot tire on the rim edge, giving necessary knowledge on the mechanical resistance of tested components. In case of the wheelchair a rear side and axle represent the weakest regions, while for the wheel a rim edge is the most loading sensitive region on the tire guard with respect to safety of the operational process. All data captured by DIC system as a function of time can be directly used for modelling and improving a suitability of the selected components since they can be employed as the limit levels during determination of safety factor. The experimental approach applied to the SUV wheel investigation can be also used as a procedure for wheels of other type vehicles tested either in laboratories of research institutions or technical universities.
Prey localization in spider orb webs using modal vibration analysis
Authors: Lott Martin , Poggetto Vinicius F. Dal , Greco Gabriele , Pugno Nicola M. , Bosia Federico
Published: November 2022

Spider webs are finely tuned multifunctional structures, widely studied for their prey capture functionalities such as impact strength and stickiness. However, they are also sophisticated sensing tools that enable the spider to precisely determine the location of impact and capture the prey before it escapes. In this paper, we suggest a new mechanism for this detection process, based on potential modal analysis capabilities of the spider, using its legs as distinct distributed point sensors. To do this, we consider a numerical model of the web structure, including asymmetry in the design, prestress, and geometrical nonlinearity effects. We show how vibration signals deriving from impacts can be decomposed into web eigenmode components, through which the spider can efficiently trace the source location. Based on this numerical analysis, we discuss the role of the web structure, asymmetry, and prestress in the imaging mechanism, confirming the role of the latter in tuning the web response to achieve an efficient prey detection instrument. The results can be relevant for efficient distributed impact sensing applications.
Understanding action concepts from videos and brain activity through subjects’ consensus
Authors: Cavazza Jacopo , Ahmed Waqar , Volpi Riccardo , Morerio Pietro , Bossi Francesco , Willemse Cesco , Wykowska Agnieszka , Murino Vittorio
Published: November 2022

In this paper, we investigate brain activity associated with complex visual tasks, showing that electroencephalography (EEG) data can help computer vision in reliably recognizing actions from video footage that is used to stimulate human observers. Notably, we consider not only typical “explicit” video action benchmarks, but also more complex data sequences in which action concepts are only referred to, implicitly. To this end, we consider a challenging action recognition benchmark dataset—Moments in Time—whose video sequences do not explicitly visualize actions, but only implicitly refer to them (e.g., fireworks in the sky as an extreme example of “flying”). We employ such videos as stimuli and involve a large sample of subjects to collect a high-definition, multi-modal EEG and video data, designed for understanding action concepts. We discover an agreement among brain activities of different subjects stimulated by the same video footage. We name it as subjects consensus, and we design a computational pipeline to transfer knowledge from EEG to video, sharply boosting the recognition performance.
WARS1, TYMP and GBP1 display a distinctive microcirculation pattern by immunohistochemistry during antibody-mediated rejection in kidney transplantation
Authors: Chauveau Bertrand , Garric Antoine , Di Tommaso Sylvaine , Raymond Anne-Aurélie , Visentin Jonathan , Vermorel Agathe , Dugot-Senant Nathalie , Déchanet-Merville Julie , Duong Van Huyen Jean-Paul , Rabant Marion , Couzi Lionel , Saltel Frédéric , Merville Pierre
Published: November 2022

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts.
Behavioral signatures of Y-like neuronal responses in human vision
Authors: Ramirez Ana L. , Thompson Lowell W. , Rosenberg Ari , Baker Curtis L.
Published: November 2022

Retinal ganglion cells initiating the magnocellular/Y-cell visual pathways respond nonlinearly to high spatial frequencies (SFs) and temporal frequencies (TFs). This nonlinearity is implicated in the processing of contrast modulation (CM) stimuli in cats and monkeys, but its contribution to human visual perception is not well understood. Here, we evaluate human psychophysical performance for CM stimuli, consisting of a high SF grating carrier whose contrast is modulated by a low SF sinewave envelope. Subjects reported the direction of motion of CM envelopes or luminance modulation (LM) gratings at different eccentricities. The performance on SF (for LMs) or carrier SF (for CMs) was measured for different TFs (LMs) or carrier TFs (CMs). The best performance for LMs was at lower TFs and SFs, decreasing systematically with eccentricity. However, performance with CMs was bandpass with carrier SF, largely independent of carrier TF, and at the highest carrier TF (20 Hz) decreased minimally with eccentricity. Since the nonlinear subunits of Y-cells respond better at higher TFs compared to the linear response components and respond best at higher SFs that are relatively independent of eccentricity, these results suggest that behavioral tasks employing CM stimuli might reveal nonlinear contributions of retinal Y-like cells to human perception.
Bioinformatics approach for the construction of multiple epitope vaccine against omicron variant of SARS-CoV-2
Authors: Zaib Sumera , Akram Fatima , Liaqat Syed Talha , Altaf Muhammad Zain , Khan Imtiaz , Dera Ayed A. , Uddin Jalal , Khan Ajmal , Al-Harrasi Ahmed
Published: November 2022

The World Health Organization categorized SARS-CoV-2 as a variant of concern, having numerous mutations in spike protein, which have been found to evade the effect of antibodies stimulated by the COVID-19 vaccine. The susceptibility to omicron variant by immunization-induced antibodies are direly required for risk evaluation. To avoid the risk of arising viral illness, the construction of a specific vaccine that triggers the production of targeted antibodies to combat infection remains highly imperative. The aim of the present study is to develop a particular vaccine exploiting bioinformatics approaches which can target B- and T-cells epitopes. Through this approach, novel epitopes of the S protein-SARS-CoV-2 were predicted for the development of a multiple epitope vaccine. Multiple epitopes were selected on the basis of toxicity, immunogenicity and antigenicity, and vaccine subunit was constructed having potential immunogenic properties. The epitopes were linked with 3 types of linker EAAAK, AAY and GPGPG for vaccine construction. Subsequently, vaccine structure was docked with the receptor and cloned in a pET-28a (+) vector. The constructed vaccine was ligated in pET-28a (+) vector in E. coli using the SnapGene tool for the expression study and a good immune response was observed. Several computational tools were used to predict and analyze the vaccine constructed by using spike protein sequence of omicrons. The current study identified a Multi-Epitope Vaccine (MEV) as a significant vaccine candidate that could potentially help the global world to combat SARS-CoV-2 infections.
Numerical investigation on the aerodynamic efficiency of bio-inspired corrugated and cambered airfoils in ground effect
Authors: Abdizadeh G. R. , Farokhinejad M. , Ghasemloo S.
Published: November 2022

This research numerically investigates the flapping motion effect on the flow around two subsonic airfoils near a ground wall. Thus far, the aerodynamic efficiency of the dragonfly-inspired flapping airfoil has not been challenged by an asymmetric cambered airfoil considering the ground effect phenomenon, especially in the MAV flight range. The analysis is carried out on the basis of an unsteady Reynolds-averaged Navier-stokes (URANS) simulation, whereby the Transition SST turbulence model simulates the flow characteristics. Dragonfly-inspired and NACA4412 airfoils are selected in this research to assess the geometry effect on aerodynamic efficiency. Moreover, the impacts of Reynolds number (Re), Strouhal number (St), and average ground clearance of the flapping airfoil are investigated. The results indicate a direct relationship between the airfoil’s aerodynamic performance ($$C_l$$Cl/$$C_d$$Cd) and the ground effect. The$$C_l$$Cl/$$C_d$$Cdincreases by reducing the airfoil and ground distance, especially at$$h_{0}=c$$h0=c. At$$Re=5\times 10^4$$Re=5×104, by increasing the St from 0.2 to 0.6, the values of$$C_l$$Cl/$$C_d$$Cddecrease from 10.34 to 2.1 and 3.22 to 1.8 for NACA4412 and dragonfly airfoils, respectively. As a result, the$$C_l$$Cl/$$C_d$$Cdof the NACA4412 airfoil is better than that of the dragonfly airfoil, especially at low oscillation frequency. The efficiency difference between the two airfoils atSt=0.6 is approximately 14%, indicating that the$$C_l$$Cl/$$C_d$$Cddifference decreases substantially with increasing frequency. For$$Re=5\times 10^3$$Re=5×103, the results show the dragonfly airfoil to have better$$C_l$$Cl/$$C_d$$Cdin all frequencies than the NACA4412 airfoil.
Frequency response characteristics and failure model of single-layered thin plate rock mass under dynamic loading
Authors: Li Feng , Wang Chenchen , Sun Runchuan , Xiang Guangyou , Ren Baorui , Zhang Zhao
Published: November 2022

In underground engineering, disturbance of dynamic load can change layered rock mass stress state and induce accidents. Traditional elastic mechanics can’t effectively solve the complex deformation problem. However, Hamiltonian mechanics system can overcome this problem. Dual variables are introduced in symplectic space to solve the deflection equations of single-layered thin plate rock mass. Comparing vibration parameters, it’s found the 1st, 5th and 6th order are effective vibration modes. The resonance characteristics of thin plate are obtained with three dynamic loads. It’s found the thin plate is most likely to resonate and damage due to the smallest resonance frequency interval and the largest vibration amplitude by impact wave and rectangular wave respectively. Then, the vibration mode of multi-layered rock mass is analyzed through Multiple Reference Impact Testing. The failure of fine sandstone is caused by the resonance of effective vibration modes by hammer excitation. Finally, the failure mechanism of thin plate is obtained by the failure theory and LS-DYNA. It’s found the four sides and corners suffer tensile shear failure and shear failure respectively. When tensile failure occurs in central, the main crack and secondary crack propagate along long axis and short axis to form “O-十” failure mode.
An integral method for determining the molecular composition of lignin and its application
Authors: Ma Qingzhi , Zhang Xuejin
Published: November 2022

Lignin is a natural and renewable aromatic polymer, but only about 2% of lignin is utilized with high added value. Polydispersity and heterogeneity are the key reasons for the difficulty in separation, fractionation, characterization, purification and utilization of lignin. However, the molecular weight of lignin is still described from the overall perspective of number-/weight-average molecular weight (Mn and Mw), which if far from enough to understand the heterogeneous and dispersed lignin. To provide a tool for understanding the molecular weight of lignin from a molecular perspective, an integral method for quantifying the molecular characteristics of lignin molecules at arbitrary molecular intervals on the molecular weight distribution curve of lignin was established. The molecular contents of wheat straw lignin as well as its soluble and insoluble fractions at different intervals were calculated. The ease of fractionation of small molecules with weights lower than 8000 g/mol into soluble fractions, and that of large molecules with weights higher than 10,000 g/mol into insoluble fractions were quantitatively analyzed. The established integral method will significantly help in the understanding the properties of lignin at the molecular-level, as well as the fractionation and utilization of lignin.
Persistent intraocular Ebola virus RNA is associated with severe uveitis in a convalescent rhesus monkey
Authors: Worwa Gabriella , Cooper Timothy K. , Yeh Steven , Shantha Jessica G. , Hischak Amanda M. W. , Klim Sarah E. , Byrum Russell , Kurtz Jonathan R. , Anthony Scott M. , Aiosa Nina M. , Ragland Danny , Lee Ji Hyun , Claire Marisa St. , Davis Carl , Ahmed Rafi , Holbrook Michael R. , Kuhn Jens H. , Saphire Erica Ollmann , Crozier Ian
Published: November 2022

Despite increasing evidence that uveitis is common and consequential in survivors of Ebola virus disease (EVD), the host-pathogen determinants of the clinical phenotype are undefined, including the pathogenetic role of persistent viral antigen, ocular tissue-specific immune responses, and histopathologic characterization. Absent sampling of human intraocular fluids and tissues, these questions might be investigated in animal models of disease; however, challenges intrinsic to the nonhuman primate model and the animal biosafety level 4 setting have historically limited inquiry. In a rhesus monkey survivor of experimental Ebola virus (EBOV) infection, we observed and documented the clinical, virologic, immunologic, and histopathologic features of severe uveitis. Here we show the clinical natural history, resultant ocular pathology, intraocular antigen-specific antibody detection, and persistent intraocular EBOV RNA detected long after clinical resolution. The association of persistent EBOV RNA as a potential driver of severe immunopathology has pathophysiologic implications for understanding, preventing, and mitigating vision-threatening uveitis in EVD survivors.