bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropsychiatric phenotypes of anti-NMDAR encephalitis: a prospective study
Authors: Espinola-Nadurille M. , Restrepo-Martínez M. , Bayliss L. , Flores-Montes E. , Rivas-Alonso V. , Vargas-Cañas S. , Hernández L. , Martínez-Juarez I. , Gonzalez-Aguilar A. , Solis-Vivanco R. , Fricchione G. L. , Flores-Rivera J. , Ramirez-Bermudez J.
Published: May 2022

Background

Patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) show a wide range of behavioral abnormalities and are often mistaken for primary psychiatric presentations. We aimed to determine the behavioral hallmarks of ANMDARE with the use of systematic neuropsychiatric and cognitive assessments.

Methods

A prospective study was conducted, with 160 patients admitted to the National Institute of Neurology and Neurosurgery of Mexico, who fulfilled criteria for possible autoimmune encephalitis and/or red flags along a time window of seven years. Cerebrospinal fluid (CSF) antibodies against the NR1 subunit of the NMDAR were processed with rat brain immunohistochemistry and cell-based assays with NMDA expressing cells. Systematic cognitive, neuropsychiatric, and functional assessments were conducted before knowing NMDAR antibodies results. A multivariate analysis was used to compare patients with and without definite ANMDARE according to antibodies in CSF.

Results

After obtaining the CSF antibodies results in 160 consecutive cases, 100 patients were positive and classified as having definite ANMDARE. The most frequent neuropsychiatric patterns were psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%). Cognition was significantly impaired. A total of 34% of the patients had a predominantly neuropsychiatric presentation without seizures. After multivariate analysis, the clinical hallmarks of ANMDARE consisted of a catatonia–delirium comorbidity, tonic-clonic seizures, and orolingual dyskinesia.

Conclusions

Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia–delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.
The booming wave of English in the linguistic landscape in Algeria
Authors: Maraf Baya , Osam Ulker Vanci
Published: May 2022

The linguistic landscape of any country reveals a lot about the linguistic identity of its citizens, especially if it is a bottom-up linguistic landscape. In Algeria, which is a multi-cultural and multi-lingual context, the linguistic landscape witnessed a remarkable shift in linguistic preferences that is represented in bottom-up signs. This shift is characterized by the addition of a new linguistic entity, English, to the Algerian linguistic landscape. In Algerian society, it is easily observed that English is not commonly present in the top-down signs assigned by the Algerian government, which contrasts with the signs of private businesses such as fashion shops, restaurants, and coffee shops. In fact, English has been found in Algerian signs since the 1990s when foreign energy companies like British Petroleum (BP) arrived and introduced the language in the country (Euromonitor, 2012), but it has become prevalent in the bottom-up signs of private businesses, which were previously dominated by other languages, i.e., Arabic and French. For those who are unfamiliar with the Algerian context, Arabic and Berber (or Tamazight) are the official languages of the country while French and English are the foreign languages. French is the first foreign language, while English is the second foreign language. Despite this clear linguistic planning, there has been unclear planning of the linguistic landscape on the part of the Algerian government, mostly in top-down signs. For instance, the government uses monolingual and bilingual signs that disregard English in the majority of signs. The monolingual signs are either Arabic or French. Berber is used in monolingual signs only in cities of Berber ethnicity. On the other hand, the bilingual signs are mostly written in Arabic and French or Arabic and Berber, the latter signs being found only in Berber-ethnicity cities such as Bejaia, Khenchela, Batna, and Tizi Ouzou. Overall, the government and Algerian citizens have rather different linguistic landscape practices since Algerians opt for integrating English, the language of globalization, presenting it in different bottom-up signs alongside other languages.
Firms as Revenue Safety Nets: Political Connections and Returns to the Chinese State
Authors: Han Chaohua , Li Xiaojun , Oi Jean C.
Published: May 2022

The political connection between the state and firms in the context of China's corporate restructuring has been little explored. Using the clientelist framework and unpacking the incentives of both firms and the state, we analyse political connections as repeated patron–client exchanges where the politically connected firms can help the state fulfil its revenue imperative, serving as a failsafe for local authorities to ensure that upper-level tax quotas are met. Leveraging original surveys of the same Chinese firms over an 11-year period and the variations in their post-restructuring board composition, we find that restructured state-owned enterprises (SOEs) with political connections pay more tax than their assessed amount, independent of profits, in exchange for more preferential access to key inputs and policy opportunities controlled by the state. Examining taxes rather than profits also offers a new interpretation for why China continues to favour its remaining SOEs even when they are less profitable.
Validity and reliability of the Spiritual Health Scale-Short Form for Turkish nursing students
Authors: Kartal Asiye , Korkmaz Aslan Gülbahar , Kılınç Eda
Published: May 2022

Objective

This study aimed at assessing the validity and reliability of the Turkish version of the Spiritual Health Scale-Short Form (SHS-SF).

Methods

The methodological research was conducted with Turkish nursing students (n= 310). The sociodemographic question form and the SHS-SF were used as data collection instruments. The Content Validity Index, Exploratory Factor Analysis (EFA), and Confirmatory Factor Analyses (CFA) were used for the validity of the scale, and Internal Consistency and Cronbach's Alpha reliability coefficient for its reliability.

Results

The EFA revealed that five factors accounted for 66.49% of the variance. According to the CFA, the factor loadings for the 24-item scale ranged from 0.40 to 0.91. Goodness-of-fit indices were as follows:χ2/df = 2.39, RMSEA = 0.06, CFI = 0.92, TLI = 0.91, IFI = 0.92. The item-total correlation for the scale items ranged from 0.37 to 0.65. The alpha coefficient for the scale was 0.91.

Significance of results

It is important to identify the level of spiritual health of nurses and nursing students with a valid and reliable scale. The SHS-SF was found to be a reliable and valid scale for use in the Turkish language and culture. The scale can be used for evaluating spiritual health levels among Turkish nurses and nursing students. This will provide an opportunity for planning appropriate interventions to improve the spiritual health level of nurses and nursing students.
The impact of mortality shocks on modelling and insurance valuation as exemplified by COVID-19
Authors: Schnürch Simon , Kleinow Torsten , Korn Ralf , Wagner Andreas
Published: May 2022

The COVID-19 pandemic interrupts the relatively steady trend of improving longevity observed in many countries over the last decades. We claim that this needs to be addressed explicitly in many mortality modelling applications, for example, in the life insurance industry. To support this position, we provide a descriptive analysis of the mortality development of several countries up to and including the year 2020. Furthermore, we perform an empirical and theoretical investigation of the impact a mortality jump has on the parameters, forecasts and implied present values of the popular Lee–Carter mortality model. We find that COVID-19 has resulted in substantial mortality shocks in many countries. We show that such shocks have a large impact on point and interval forecasts of death rates and, consequently, on the valuation of mortality-related insurance products. We obtain similar findings under the Cairns–Blake–Dowd mortality model, which demonstrates that the effects caused by COVID-19 show up in a variety of models. Finally, we provide an overview of approaches to handle extreme mortality events such as the COVID-19 pandemic in mortality modelling.
Fill level measurements using an M-sequence UWB radar
Authors: Wegner Tim Erich , Gebhardt Stefan , Del Galdo Giovanni
Published: May 2022

Due to increasingly complex and automated manufacturing processes, the demands on the control parameters of these processes are also increasing. In many applications, such a parameter is the fill quantity, whose precise determination is of ever growing importance. This paper shows with which accuracy and precision an M-sequence ultra-wideband radar can determine levels in small metallic and non-metallic containers with contact-based and contactless measurements. First, the principle of level measurement using guided wave radar is explained and the measurement setup is described. Afterward, the measurement results are shown and discussed. The measurements show that the level can be measured with an accuracy of better than 0.5 mm. In addition, level fluctuations can be detected with a precision of 3 ${\rm \mu }$m. Based on the results of the guided wave radar, the possibilities of volumetric contactless measurement using an electrically small patch antenna are discussed. A particular challenge in contactless level measurement is the high number of multipath components, which strongly influence the accuracy. In addition, there are near-field effects when measuring close to the antenna. Exploiting these near-field effects, an additional method to accurately determine the full state of the container is investigated.
Global, regional and national burden of autism spectrum disorder from 1990 to 2019: results from the Global Burden of Disease Study 2019
Authors: Li Zhen , Yang Lejin , Chen Hui , Fang Yuan , Zhang Tongchao , Yin Xiaolin , Man Jinyu , Yang Xiaorong , Lu Ming
Published: May 2022

Aims

Autism spectrum disorder (ASD) is a neurodevelopmental condition, with symptoms appearing in the early developmental period. Little is known about its current burden at the global, regional and national levels. This systematic analysis aims to summarise the latest magnitudes and temporal trends of ASD burden, which is essential to facilitate more detailed development of prevention and intervention strategies.

Methods

The data on ASD incidence, prevalence, disability-adjusted life years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease Study 2019. The average annual percentage change was calculated to quantify the secular trends in age-standardised rates (ASRs) of ASD burden by region, sex and age.

Results

In 2019, there were an estimated 60.38 × 104 [95% uncertainty interval (UI) 50.17–72.01] incident cases of ASD, 283.25 × 105 (95% UI 235.01–338.11) prevalent cases and 43.07 × 105 (95% UI 28.22–62.32) DALYs globally. The ASR of incidence slightly increased by around 0.06% annually over the past three decades, while the ASRs of prevalence and DALYs both remained stable over the past three decades. In 2019, the highest burden of ASD was observed in high-income regions, especially in high-income North America, high-income Asia Pacific and Western Europe, where a significant growth in ASRs was also observed. The ASR of ASD burden in males was around three times that of females, but the gender difference was shrunk with the pronounced increase among females. Of note, among the population aged over 65 years, the burden of ASD presented increasing trends globally.

Conclusions

The global burden of ASD continues to increase and remains a major mental health concern. These substantial heterogeneities in ASD burden worldwide highlight the need for making suitable mental-related policies and providing special social and health services.
Heritability of Age at Menarche in Nigerian Adolescent Twins
Authors: Hur Yoon-Mi , Ra Jong-Min
Published: May 2022

Heritability of age at menarche (AAM) in African populations remains largely unknown. A question on AAM was given to 1803 [454 monozygotic (MZ), 823 same-sex dizygotic (DZ), and 526 female members of opposite sex] adolescent twins attending public schools in Lagos State, Nigeria. The age range of the sample was 12–18 years, with a mean (SD) of 14.57 (±1.70) years. The data included 905 missing cases consisting of those who had not experienced menarche and did not recall AAM. Missing values were imputed using the Expectation-Maximization algorithm. Kaplan–Meier analysis based on the imputed data yielded 13.23 years [95% CI [13.18, 13.28] for the mean and 13.00 years [95% CI [12.96, 13.04] for the median of AAM. Twin correlation and model-fitting analyses were performed on the basis of those who reported AAM (MZ = 82 complete pairs and 38 cotwin missing cases; DZ = 157 complete pairs and 99 cotwin missing cases). Maximum likelihood MZ and DZ twin correlations for AAM were .63 (95% CI [.48, .74]) and .33 (95% CI [.19, .45]) respectively. Model-fitting analyses indicated that 58% (95% CI [46, 67]) of the variance of AAM was associated with additive genetic influences with the remaining variance, 42% (33−54) being due to nonshared environmental influences including measurement error. The heritability estimate found in this study was within the range of those found in Asian and Western twin samples.
Interaction between 4-hydroxyphenylpyruvate dioxygenase–inhibiting and reactive oxygen species–generating herbicides for the control of annual weed species in corn
Authors: Fluttert John C. , Soltani Nader , Galla Mariano , Hooker David C. , Robinson Darren E. , Sikkema Peter H.
Published: May 2022

The complementary modes of action of 4-hydroxyphenylpyruvate dioxygenase (HPPD) and photosystem II (PSII) inhibitors have been credited for the synergistic weed control improvement of several species. Recent research discovered that reactive oxygen species (ROS) generation and subsequent lipid peroxidation is the cause of cell death by the glutamine synthetase inhibitor glufosinate. Therefore, a basis for synergy exists between glufosinate and HPPD inhibitors, but the interaction has not been well reported. Four field experiments were conducted in Ontario, Canada, in 2020 and 2021 to determine the interaction between HPPD-inhibiting (mesotrione and tolpyralate) and ROS-generating (atrazine, bromoxynil, bentazon, and glufosinate) herbicides on control of annual weed species in corn (Zea mays L.). The ROS generators were synergistic with the HPPD inhibitors and provided ≥95% control of velvetleaf (Abutilon theophrasti Medik.), except for tolpyralate + glufosinate, which was additive at 8 wk after application (WAA) and provided 87% control. Tank mixes of HPPD inhibitors plus ROS generators were synergistic for the control of common ragweed (Ambrosia artemisiifolia L.), except for tolpyralate + glufosinate, which was antagonistic at 8 WAA. Tolpyralate + glufosinate was antagonistic for the control of barnyardgrass [Echinochloa crus-galli (L.) P. Beauv.] and Setaria spp. at 8 WAA. Common lambsquarters (Chenopodium album L.) control at 8 WAA was synergistic and ≥95% with mesotrione plus atrazine, bromoxynil, or glufosinate and with tolpyralate plus bromoxynil or bentazon. Herbicide tank mixes were generally additive for the control of wild mustard (Sinapis arvensis L.) at 8 WAA, except for the synergistic tank mixes of tolpyralate plus atrazine or bromoxynil; however, each tank mix provided 97% to 100% control of S. arvensis. Results from this study demonstrate that co-application of ROS generators with mesotrione or tolpyralate controlled all broadleaf weed species >90% at 8 WAA, with the exceptions of A. artemisiifolia and C. album control with tolpyralate + glufosinate. Mesotrione plus PSII inhibitors controlled E. crus-galli and Setaria spp. 48 to 68 percentage points less than tolpyralate plus the respective PSII inhibitor at 8 WAA; however, mesotrione + glufosinate and tolpyralate + glufosinate controlled the grass weed species similarly.
Penetration of Ultraviolet‐B Radiation in Oligotrophic Regions of the Oceans During the Malaspina 2010 Expedition
Authors: Overmans S. , Duarte C. M. , Sobrino C. , Iuculano F. , Álvarez‐Salgado X. A. , Agustí S.
Published: May 2022

Few studies have investigated ultraviolet (UV) radiation in the open ocean besides its harmful effects on organisms and influence on biogeochemical processes. Here, we assessed UV attenuation, with particular focus on UV‐B, across the (sub)tropical ocean during the Malaspina 2010 Circumnavigation. Vertical UV radiometer profiles together with Chl‐a concentration, and UV absorption by CDOM (aCDOM(λ)) and by suspended particulate matter (ap(λ)) were measured at 117 stations. At photosynthetically active radiation (PAR) and across UV‐A and UV‐B wavelengths, the lowest downwelling attenuation coefficients (Kd) during the expedition were recorded in ultra‐oligotrophic regions at 5°–15°S (mean Kd(305 nm): 0.129 m−1, mean Kd(313 nm): 0.107 m−1) in the Indian and South Pacific Oceans. The waters here were comparatively more transparent than at 5°–15°N (mean Kd(305 nm): 0.239 m−1, mean Kd(313 nm): 0.181 m−1) where equatorial upwelling occurs. Kd was highest near the Costa Rica Dome (Kd(313 nm): 0.226 m−1) and at the confluence of the Benguela and Agulhas currents (Kd(313 nm): 0.251 m−1). The contribution of ap(λ) toward nonwater absorption (anw(λ)) was significantly lower at 305 nm than at 313 and 320 nm, suggesting the contribution of absorption by detritus and phytoplankton particles decreases compared with that of CDOM absorption as UV‐B wavelength decreases. Both aCDOM(λ) and ap(λ) at UV‐B wavelengths were lowest in the Indian Ocean whereas Kd was lowest in the South Pacific. This finding emphasizes that other factors besides absorption, such as scattering by reflective phytoplankton or inorganic particles, strongly influence UV‐B attenuation in open ocean waters.
Diurnal Evolution of Cloud Water Responses to Aerosols
Authors: Rahu J. , Trofimov H. , Post P. , Toll V.
Published: May 2022

Clouds play an essential role in the global energy budget, but the impact of anthropogenic aerosols on clouds is still poorly understood. We use 15‐min temporal resolution geostationary satellite data to study the temporal evolution of polluted cloud tracks detected in the European part of Russia. Previous analysis of polluted cloud tracks shows that cloud water response to aerosols is bidirectional. Here, we show that cloud water gradually increases in the afternoon for polluted clouds in some cases. Aerosol‐induced cloud thickening is much more likely in the case of thin unpolluted clouds. However, on average, there is less cloud water in the polluted clouds compared to the nearby unpolluted clouds. The temporal evolution of cloud thinning is not observed, and polluted clouds are thinner than the nearby unpolluted clouds since the early morning. The physical mechanisms leading to the observed changes and the influence of retrieval bias on the detected changes need further clarification. Our findings highlight the need to research the temporal evolution of cloud responses to aerosols to estimate the aerosol radiative forcing more accurately.
Dynamics of Ocean Worlds Likely Controlled by Their Rotation
Authors: Rehnberg Morgan
Published: May 2022

New simulations suggest that subsurface oceans on icy moons with small natural Rossby numbers may be dominated by rotational effects.
Contrasting State‐Dependent Effects of Natural Forcing on Global and Local Climate Variability
Authors: Ellerhoff Beatrice , Kirschner Moritz J. , Ziegler Elisa , Holloway Max D. , Sime Louise , Rehfeld Kira
Published: May 2022

Natural forcing from solar and volcanic activity contributes significantly to climate variability. The post‐eruption cooling of strong volcanic eruptions was hypothesized to have led to millennial‐scale variability during Glacials. Cooling induced by volcanic eruption is potentially weaker in the warmer climate. The underlying question is whether the climatic response to natural forcing is state‐dependent. Here, we quantify the response to natural forcing under Last Glacial and Pre‐Industrial conditions in an ensemble of climate model simulations. We evaluate internal and forced variability on annual to multicentennial scales. The global temperature response reveals no state dependency. Small local differences result mainly from state‐dependent sea ice changes. Variability in forced simulations matches paleoclimate reconstructions significantly better than in unforced scenarios. Considering natural forcing is therefore important for model‐data comparison and future projections.
Problems With the Shoreline Development Index—A Widely Used Metric of Lake Shape
Authors: Seekell D. , Cael B. B. , Byström P.
Published: May 2022

The shoreline development index—The ratio of a lake’s shore length to the circumference of a circle with the lake’s area—Is a core metric of lake morphometry used in Earth and planetary sciences. In this paper, we demonstrate that the shoreline development index is scale‐dependent and cannot be used to compare lakes with different areas. We show that large lakes will have higher shoreline development index measurements than smaller lakes of the same characteristic shape, even when mapped at the same scale. Specifically, the shoreline development index increases by about 14% for each doubling of lake area. These results call into question previously reported patterns of lake shape. We provide several suggestions to improve the application of this index, including a bias‐corrected formulation for comparing lakes with different surface areas.
Nonlinear Wave Growth of Whistler‐Mode Hiss Emissions in a Uniform Magnetic Field
Authors: Liu Yin , Omura Yoshiharu
Published: May 2022

We conduct electromagnetic particle simulations in a uniform magnetic environment to verify the nonlinear wave growth process of plasmaspheric hiss in the equatorial plasmasphere. The satisfaction of the separability criterion for coexisting multiple frequency waves in the initial stage of wavenumber‐time evolution declares that wave packets are coherent and capable of growing nonlinearly. Spatial and temporal evolutions of two typical modes located in wavenumber‐time evolution demonstrate the consistency among wave growths, frequency variations, and inhomogeneity factor S in coherent wave packets, showing that rising and falling tones occur at negative and positive S values, respectively, and an obvious wave growth happens in a reasonable range of S satisfying the second‐order resonance condition. Wave packets extracted from wave fields in space and time by a frequency band‐pass filter confirm a good agreement between the nonlinear theory and simulation results. The nonlinear growth rates of the extracted wave packets possess similar magnitudes to the growth rates of wave packets in the simulation, and they are much greater than the theoretical linear growth rate, indicating that the nonlinear process is essential in the generation of plasmaspheric hiss.
African Hydroclimate During the Early Eocene From the DeepMIP Simulations
Authors: Williams Charles J. R. , Lunt Daniel J. , Salzmann Ulrich , Reichgelt Tammo , Inglis Gordon N. , Greenwood David R. , Chan Wing‐Le , Abe‐Ouchi Ayako , Donnadieu Yannick , Hutchinson David K. , de Boer Agatha M. , Ladant Jean‐Baptiste , Morozova Polina A. , Niezgodzki Igor , Knorr Gregor , Steinig Sebastian , Zhang Zhongshi , Zhu Jiang , Huber Matthew , Otto‐Bliesner Bette L.
Published: May 2022

The early Eocene (∼56–48 Myr ago) is characterized by high CO2 estimates (1,200–2,500 ppmv) and elevated global temperatures (∼10°C–16°C higher than modern). However, the response of the hydrological cycle during the early Eocene is poorly constrained, especially in regions with sparse data coverage (e.g., Africa). Here, we present a study of African hydroclimate during the early Eocene, as simulated by an ensemble of state‐of‐the‐art climate models in the Deep‐time Model Intercomparison Project (DeepMIP). A comparison between the DeepMIP pre‐industrial simulations and modern observations suggests that model biases are model‐ and geographically dependent, however, these biases are reduced in the model ensemble mean. A comparison between the Eocene simulations and the pre‐industrial suggests that there is no obvious wetting or drying trend as the CO2 increases. The results suggest that changes to the land sea mask (relative to modern) in the models may be responsible for the simulated increases in precipitation to the north of Eocene Africa. There is an increase in precipitation over equatorial and West Africa and associated drying over northern Africa as CO2 rises. There are also important dynamical changes, with evidence that anticyclonic low‐level circulation is replaced by increased south‐westerly flow at high CO2 levels. Lastly, a model‐data comparison using newly compiled quantitative climate estimates from paleobotanical proxy data suggests a marginally better fit with the reconstructions at lower levels of CO2.
FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1
Authors: Zhao Xinyuan , Chen Huan , Qiu Yu , Cui Li
Published: May 2022

Head and neck squamous cell carcinoma (HNSCC) still lacks effective targeted treatment. Therefore, exploring novel and robust molecular targets is critical for improving the clinical outcome of HNSCC. Here, we reported that the expression levels of family with sequence similarity 64, member A (FAM64A) were significantly higher in HNSCC tissues and cell lines. In addition, FAM64A overexpression was found to be strongly associated with an unfavorable prognosis of HNSCC. Both in vitro and in vivo evidence showed that FAM64A depletion suppressed the malignant activities of HNSCC cells, and vice versa. Moreover, we found that the FAM64A level was progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic 4-nitroquinoline-1-oxide mouse model. Mechanistically, a physical interaction was found between FAM64A and forkhead box protein M1 (FOXM1) in HNSCC cells. FAM64A promoted HNSCC tumorigenesis not only by enhancing the transcriptional activity of FOXM1, but also, more importantly, by modulating FOXM1 expression via the autoregulation loop. Furthermore, a positive correlation between FAM64A and FOXM1 was found in multiple independent cohorts. Taken together, our findings reveal a previously unknown mechanism behind the activation of FOXM1 in HNSCC, and FAM64A might be a promising molecular therapeutic target for treating HNSCC.
Single-shot circular dichroism spectroscopy
Authors: Karabchevsky Alina
Published: May 2022

Circular dichroism spectroscopy can be optimized to measure the scattering circular dichroism response of a single chiral nanostructure with a single shot.
The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites
Authors: Hedderich Janik B. , Persechino Margherita , Becker Katharina , Heydenreich Franziska M. , Gutermuth Torben , Bouvier Michel , Bünemann Moritz , Kolb Peter
Published: May 2022

G-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into the focus as potential binding sites for synthetic modulators. Here, to better characterise such pockets, we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting the ensemble of binding locations to pocket-defining volumes. Our analysis confirms all previously identified pockets and reveals nine previously untargeted sites. In order to test for the feasibility of functional modulation of receptors through binding of a ligand to such sites, we mutate residues in two sites, in two model receptors, the muscarinic acetylcholine receptor M3andβ2-adrenergic receptor. Moreover, we analyse the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites.
EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Authors: Zhang Lin , Qu Jingkun , Qi Yutao , Duan Yimin , Huang Yu-Wen , Zhou Zhifen , Li Ping , Yao Jun , Huang Beibei , Zhang Shuxing , Yu Dihua
Published: May 2022

Bone metastases occur in 50–70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2(EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn’t been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increasesITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer.
Cumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host
Authors: Sonnleitner Sissy Therese , Prelog Martina , Sonnleitner Stefanie , Hinterbichler Eva , Halbfurter Hannah , Kopecky Dominik B. C. , Almanzar Giovanni , Koblmüller Stephan , Sturmbauer Christian , Feist Leonard , Horres Ralf , Posch Wilfried , Walder Gernot
Published: May 2022

Different scenarios explaining the emergence of novel variants of concern (VOC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including their evolution in scarcely monitored populations, in animals as alternative hosts, or in immunocompromised individuals. Here we report SARS-CoV-2 immune escape mutations over a period of seven months in an immunocompromised patient with prolonged viral shedding. Signs of infection, viral shedding and mutation events are periodically analyzed using RT-PCR and next-generation sequencing based on naso-pharyngeal swabs, with the results complemented by immunological diagnostics to determine humoral and T cell immune responses. Throughout the infection course, 17 non-synonymous intra-host mutations are noted, with 15 (88.2%) having been previously described as prominent immune escape mutations (S:E484K, S:D950N, S:P681H, S:N501Y, S:del(9), N:S235F and S:H655Y) in VOCs. The high frequency of these non-synonymous mutations is consistent with multiple events of convergent evolution. Thus, our results suggest that specific mutations in the SARS-CoV-2 genome may represent positions with a fitness advantage, and may serve as targets in future vaccine and therapeutics development for COVID-19.
Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer
Authors: Zhou Liyuan , Qiu Qiongzi , Zhou Qing , Li Jianwei , Yu Mengqian , Li Kezhen , Xu Lingling , Ke Xiaohui , Xu Haiming , Lu Bingjian , Wang Hui , Lu Weiguo , Liu Pengyuan , Lu Yan
Published: May 2022

Integration of human papillomavirus (HPV) DNA into the human genome is considered as a key event in cervical carcinogenesis. Here, we perform comprehensive characterization of large-range virus-human integration events in 16 HPV16-positive cervical tumors using the Nanopore long-read sequencing technology. Four distinct integration types characterized by the integrated HPV DNA segments are identified with Type B being particularly notable as lacking E6/E7 genes. We further demonstrate that multiple clonal integration events are involved in the use of shared breakpoints, the induction of inter-chromosomal translocations and the formation of extrachromosomal circular virus-human hybrid structures. Combined with the corresponding RNA-seq data, we highlight LINC00290, LINC02500 and LENG9 as potential driver genes in cervical cancer. Finally, we reveal the spatial relationship of HPV integration and its various structural variations as well as their functional consequences in cervical cancer. These findings provide insight into HPV integration and its oncogenic progression in cervical cancer.
Profiling of hMPV F-specific antibodies isolated from human memory B cells
Authors: Xiao Xiao , Fridman Arthur , Zhang Lu , Pristatsky Pavlo , Durr Eberhard , Minnier Michael , Tang Aimin , Cox Kara S. , Wen Zhiyun , Moore Renee , Tian Dongrui , Galli Jennifer D. , Cosmi Scott , Eddins Michael J. , Sullivan Nicole L. , Yan Xiaodong , Bett Andrew J. , Su Hua-Poo , Vora Kalpit A. , Chen Zhifeng , Zhang Lan
Published: May 2022

Human metapneumovirus (hMPV) belongs to thePneumoviridaefamily and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors. We characterize the antibodies’ germline usage, epitopes, neutralization potencies, and binding specificities. We find that unlike RSV-F specific mAbs, antibody responses to hMPV F are less dominant against the apex of the antigen, and the majority of the potent neutralizing mAbs recognize epitopes on the side of hMPV F. Furthermore, neutralizing epitopes that differ from previously defined antigenic sites on RSV F are identified, and multiple binding modes of site V and II mAbs are discovered. Interestingly, mAbs that bind preferentially to the unprocessed prefusion F show poor neutralization potency. These results elucidate the immune recognition of hMPV infection and provide novel insights for future hMPV antibody and vaccine development.
Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer
Authors: Li Zheqi , Spoelstra Nicole S. , Sikora Matthew J. , Sams Sharon B. , Elias Anthony , Richer Jennifer K. , Lee Adrian V. , Oesterreich Steffi
Published: May 2022

BothTP53andESR1mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity betweenTP53andESR1mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay betweenTP53andESR1mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features.ESR1mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression inTP53mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences ofTP53andESR1mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity betweenESR1andTP53mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.
Uncertainty about others’ trustworthiness increases during adolescence and guides social information sampling
Authors: Ma I. , Westhoff B. , van Duijvenvoorde A. C. K.
Published: May 2022

Adolescence is a key life phase for developing well-adjusted social behaviour. An essential component of well-adjusted social behaviour is the ability to update our beliefs about the trustworthiness of others based on gathered information. Here, we examined how adolescents (n = 157, 10–24 years) sequentially sampled information about the trustworthiness of peers and how they used this information to update their beliefs about others’ trustworthiness. Our Bayesian computational modelling approach revealed an adolescence-emergent increase in uncertainty of prior beliefs about others’ trustworthiness. As a consequence, early to mid-adolescents (ages 10–16) gradually relied less on their prior beliefs and more on the gathered evidence when deciding to sample more information, and when deciding to trust. We propose that these age-related differences could be adaptive to the rapidly changing social environment of early and mid-adolescents. Together, these findings contribute to the understanding of adolescent social development by revealing adolescent-emergent flexibility in prior beliefs about others that drives adolescents’ information sampling and trust decisions.
Novel mobility index tracks COVID-19 transmission following stay-at-home orders
Authors: Her Peter Hyunwuk , Saeed Sahar , Tram Khai Hoan , Bhatnagar Sahir R
Published: May 2022

Considering the emergence of SARS-CoV-2 variants and low vaccine access and uptake, minimizing human interactions remains an effective strategy to mitigate the spread of SARS-CoV-2. Using a functional principal component analysis, we created a multidimensional mobility index (MI) using six metrics compiled by SafeGraph from all counties in Illinois, Ohio, Michigan and Indiana between January 1 to December 8, 2020. Changes in mobility were defined as a time-updated 7-day rolling average. Associations between our MI and COVID-19 cases were estimated using a quasi-Poisson hierarchical generalized additive model adjusted for population density and the COVID-19 Community Vulnerability Index. Individual mobility metrics varied significantly by counties and by calendar time. More than 50% of the variability in the data was explained by the first principal component by each state, indicating good dimension reduction. While an individual metric of mobility was not associated with surges of COVID-19, our MI was independently associated with COVID-19 cases in all four states given varying time-lags. Following the expiration of stay-at-home orders, a single metric of mobility was not sensitive enough to capture the complexity of human interactions. Monitoring mobility can be an important public health tool, however, it should be modelled as a multidimensional construct.
Memory-inspired spiking hyperdimensional network for robust online learning
Authors: Zou Zhuowen , Alimohamadi Haleh , Zakeri Ali , Imani Farhad , Kim Yeseong , Najafi M. Hassan , Imani Mohsen
Published: May 2022

Recently, brain-inspired computing models have shown great potential to outperform today’s deep learning solutions in terms of robustness and energy efficiency. Particularly, Spiking Neural Networks (SNNs) and HyperDimensional Computing (HDC) have shown promising results in enabling efficient and robust cognitive learning. Despite the success, these two brain-inspired models have different strengths. While SNN mimics the physical properties of the human brain, HDC models the brain on a more abstract and functional level. Their design philosophies demonstrate complementary patterns that motivate their combination. With the help of the classical psychological model on memory, we propose SpikeHD, the first framework that fundamentally combines Spiking neural network and hyperdimensional computing. SpikeHD generates a scalable and strong cognitive learning system that better mimics brain functionality. SpikeHD exploits spiking neural networks to extract low-level features by preserving the spatial and temporal correlation of raw event-based spike data. Then, it utilizes HDC to operate over SNN output by mapping the signal into high-dimensional space, learning the abstract information, and classifying the data. Our extensive evaluation on a set of benchmark classification problems shows that SpikeHD provides the following benefit compared to SNN architecture: (1) significantly enhance learning capability by exploiting two-stage information processing, (2) enables substantial robustness to noise and failure, and (3) reduces the network size and required parameters to learn complex information.
Importance of vaccine action and availability and epidemic severity for delaying the second vaccine dose
Authors: Berec Luděk , Levínský René , Weiner Jakub , Šmíd Martin , Neruda Roman , Vidnerová Petra , Suchopárová Gabriela
Published: May 2022

Following initial optimism regarding potentially rapid vaccination, delays and shortages in vaccine supplies occurred in many countries during spring 2021. Various strategies to counter this gloomy reality and speed up vaccination have been set forth, of which the most popular has been to delay the second vaccine dose for a longer period than originally recommended by the manufacturers. Controversy has surrounded this strategy, and overly simplistic models have been developed to shed light on this issue. Here we use three different epidemic models, all accounting for then actual COVID-19 epidemic in the Czech Republic, including the real vaccination rollout, to explore when delaying the second vaccine dose by another 3 weeks from 21 to 42 days is advantageous. Using COVID-19-related deaths as a quantity to compare various model scenarios, we find that the way of vaccine action at the beginning of the infection course (preventing infection and symptoms appearance), mild epidemic and sufficient vaccine supply rate call for the original inter-dose period of 21 days regardless of vaccine efficacy. On the contrary, for the vaccine action at the end of infection course (preventing severe symptoms and death), severe epidemic and low vaccine supply rate, the 42-day inter-dose period is preferable, at any plausible vaccine efficacy.
Exploring selective autophagy events in multiple biologic models using LC3-interacting regions (LIR)-based molecular traps
Authors: Quinet Grégoire , Génin Pierre , Ozturk Oznur , Belgareh-Touzé Naima , Courtot Lilas , Legouis Renaud , Weil Robert , Cohen Mickael M. , Rodriguez Manuel S.
Published: May 2022

Autophagy is an essential cellular pathway that ensures degradation of a wide range of substrates including damaged organelles or large protein aggregates. Understanding how this proteolytic pathway is regulated would increase our comprehension on its role in cellular physiology and contribute to identify biomarkers or potential drug targets to develop more specific treatments for disease in which autophagy is dysregulated. Here, we report the development of molecular traps based in the tandem disposition of LC3-interacting regions (LIR). The estimated affinity of LC3-traps for distinct recombinant LC3/GABARAP proteins is in the low nanomolar range and allows the capture of these proteins from distinct mammalian cell lines, S. cerevisiae and C. elegans. LC3-traps show preferences for GABARAP/LGG1 or LC3/LGG2 and pull-down substrates targeted to proteaphagy and mitophagy. Therefore, LC3-traps are versatile tools that can be adapted to multiple applications to monitor selective autophagy events in distinct physiologic and pathologic circumstances.
Novel fabrication of hydrophobic/oleophilic human hair fiber for efficient oil/water separation through one-pot dip-coating synthesis route
Authors: Chenxi Yang , Jian Wang , Haiou Zhang , Tingting Cao , Hang Zhou , Jiawei Wang , Bo Bai
Published: May 2022

Frequent oil spill accidents and industrial wastewater discharge has always been one of the most severe worldwide environmental problems. To cope with this problem, many fluorine-containing and high-cost materials with superwettability have been extensively applied for oil–water separation, which hinders its large-scale application. In this work, a novel human hair fiber (HHF)-polymerized octadecylsiloxane (PODS) fiber was fabricated with a facile one-pot dip-coating synthesis approach, inspired by the self-assembly performance and hydrophobicity of OTS modification. The benefits of prominent hydrophobic/lipophilic behavior lie in the low surface energy, and a rough PODS coating was rationally adhered on the surface of HHF. Driven solely by gravity and capillary force, the HHF-PODS showed excellent oil/water separation efficiency (> 99.0%) for a wide range of heavy and light oil/water mixtures. In addition, HHF-PODS demonstrated durability toward different harsh environments like alkaline, acid, and salty solutions.
Potential cosmeceutical lamellar liquid crystals containing black longan (Dimocarpus longan Lour.) seed extract for MMP-1 and hyaluronidase inhibition
Authors: Hong-in Preaploy , Chaiyana Wantida
Published: May 2022

The aims of this study were to evaluate the biological activities of black Dimocarpus longan Lour. seed extracts and develop a lamellar liquid crystal (LLC). Different solvents, including petroleum ether, ethyl acetate, and 95% v/v ethanol, were used in the maceration of black D. longan seeds. The inhibitory activities on matrix metalloproteinase-1 (MMP-1) and hyaluronidase were evaluated. The irritating potency of D. longan seed extracts was determined using the hen's egg chorioallantoic membrane test. The extract with the strongest anti-ageing activities and no irritant impact was examined for its chemical contents using high-performance liquid chromatography and incorporated into the LLC. Various factors affecting the LLC formulations, including surfactant types and amounts, thickening agent types and amounts, and various oil types, were investigated. The results demonstrated that the ethyl acetate extract (EtOAc) was the most potent inhibitor of MMP-1 (IC50 = 21.7 ± 5.4 µg/mL) and hyaluronidase (oleanolic acid equivalent = 0.44 ± 0.03 g per g extract). Interestingly, its MMP-1 inhibition was equivalent to that of oleanolic acid, corilagin, and gallic acid. Furthermore, its hyaluronidase inhibition was equivalent to that of gallic acid and ellagic acid. Gallic acid, which was the most abundant compound (15.6% ± 0.06% w/w) was suggested as the compound responsible for the biological activities of EtOAc extract. Considering its potential anti-skin ageing properties with no irritation of EtOAc extract, it was incorporated into the most suitable LLC, which was composed of 5% w/w Lexfeel® D5 oil, 0.5% w/w Carbopol® U21, 2% w/w Liquid Crystal Cream Maker, and 92.5% w/w DI water. The LLC containing EtOAc extract presented birefringence under a polarizing light microscope, indicating its crystallinity. The formulation had good stability after heating–cooling cycles in terms of external appearance, crystallinity, viscosity, and pH (5.5). As a result, it is recommended as a potential cosmeceutical formulation for anti-skin wrinkling. It is proposed that more research be conducted on the safety and efficacy of the treatment on human volunteers.