bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers of hypoxic–ischemic encephalopathy: a systematic review
Authors: Caramelo Inês , Coelho Margarida , Rosado Miguel , Cardoso Carla M. P. , Dinis Alexandra , Duarte Carlos B. , Grãos Mário , Manadas Bruno
Published: April 2023

Background

Current diagnostic criteria for hypoxic–ischemic encephalopathy in the early hours lack objective measurement tools. Therefore, this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice (PROSPERO ID: CRD42021272610).

Data sources

Searches were performed in PubMed, Web of Science, and Science Direct databases until November 2020. English original papers analyzing samples from newborns > 36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included. Bias was assessed by the Newcastle–Ottawa Scale. The search and data extraction were verified by two authors separately.

Results

From 373 papers, 30 met the inclusion criteria. Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia. In addition, the levels of glial fibrillary acidic protein, ubiquitin carboxyl terminal hydrolase isozyme-L1, glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with hypoxic–ischemic encephalopathy. Moreover, pathway analysis revealed insulin-like growth factor signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult.

Conclusions

Neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of hypoxic–ischemic encephalopathy newborns. However, more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.
On the Philosophy of Unsupervised Learning
Authors: Watson David S.
Published: April 2023

Unsupervised learning algorithms are widely used for many important statistical tasks with numerous applications in science and industry. Yet despite their prevalence, they have attracted remarkably little philosophical scrutiny to date. This stands in stark contrast to supervised and reinforcement learning algorithms, which have been widely studied and critically evaluated, often with an emphasis on ethical concerns. In this article, I analyze three canonical unsupervised learning problems: clustering, abstraction, and generative modeling. I argue that these methods raise unique epistemological and ontological questions, providing data-driven tools for discovering natural kinds and distinguishing essence from contingency. This analysis goes some way toward filling the lacuna in contemporary philosophical discourse on unsupervised learning, as well as bringing conceptual unity to a heterogeneous field more often described by what it isnot(i.e., supervised or reinforcement learning) than by what itis. I submit that unsupervised learning is not just a legitimate subject of philosophical inquiry but perhaps the most fundamental branch of all AI. However, an uncritical overreliance on unsupervised methods poses major epistemic and ethical risks. I conclude by advocating for a pragmatic, error-statistical approach that embraces the opportunities and mitigates the challenges posed by this powerful class of algorithms.
Deepening the understanding of the structural validity of the Tilburg Frailty Indicator
Authors: Balasch-Bernat Mercè , Sentandreu-Mañó Trinidad , Tomás José M. , Cebrià i Iranzo Maria A. , Tortosa-Chuliá Maria A. , Arnal-Gómez Anna , Cezón-Serrano Natalia
Published: April 2023

Background

Psychometric properties of the Tilburg Frailty Indicator (TFI) have shown low internal consistency for psychological and social domains, and evidence for its structure validity is controversial. Moreover, research on TFI is frequently limited to community dwellings.

Aims

To evaluate structural validity, reliability, and convergent and divergent validity of the Spanish version of the Tilburg Frailty Indicator (TFI) in both community-dwelling and institutionalized older people.

Materials and methods

A cross-sectional study was conducted on Spanish older adults (n = 457) recruited from both community settings (n = 322) and nursing homes (n = 135). Participants completed the TFI and other frailty instruments: Fried’s Frailty Phenotype, Edmonton Frailty Scale, FRAIL Scale, and Kihon Checklist (KCL). Confirmatory Factor Analysis (CFA), and reliability and validity coefficients were estimated.

Results and discussion

Some items from physical and social domains showed low factor loadings (< 0.40). The three-factor CFA model showed better fit indices after depurating these items. Reliability estimates were good (CRI ≥ 0.70) for physical and psychological domains in the institutionalized sample, while in the community dwellings, only physical domain reliability was adequate. Convergent and divergent validity of physical and psychological domains was good, except for some alternative psychological measures highly correlating with the TFI physical component (KCL-depressive mood and Edmonton mood). However, the social domain showed low correlations with some social indicators.

Conclusion

The findings of this study clarify some of the controversial validation results of the TFI structure and provide evidence to improve its use in psychometric terms.

Clinical trial registration number

NCT03832608.
Characterization of reading errors in languages with different orthographic regularity: an Italian–English comparison
Authors: Marinelli Chiara Valeria , Romani Cristina , McGowan Victoria A. , Giustizieri Simona , Zoccolotti Pierluigi
Published: April 2023

The study examined whether a classification of errors based on Hendriks and Kolk’s (1997) proposal would effectively characterize the reading profile of children learning two orthographies varying for regularity, such as Italian and English. The study considered both an age-match and a grade-match comparison. Offline analysis of error production was carried out for two lists of stimuli: List 1 including regular words varying for frequency and matched non-words and List 2 including low-frequency words varying for regularity. In List 1, Italian-reading children made more multiple attempts characterized by a slow and progressive approach to the target (sounding-out behavior) than English-reading children, while the latter made relatively more word substitutions and non-word lexicalizations. As for List 2, Italian-reading children made relatively more multiple attempts and progressive approaches to the target compared to the English-reading children (with more sounding-out behaviors and syllabications), while the opposite occurred for phonological-visual errors, word substitutions, morphological, and semantic errors. Both groups showed a high proportion of phonological-visual and regularization errors (stress assignment in the case of Italian-reading children). Overall, the use of an error coding system specifically tuned to the characteristics of the orthographies investigated allowed a more comprehensive identification of reading difficulties which allowed the different strategies used by children of different languages to emerge more clearly (more reliance on sub-lexical routines in Italian readers and on lexical routines in English readers). These results call for more attention to error patterns in the identification of reading difficulties in children of different languages including those learning a transparent orthography where error analyses have largely been ignored.
The Evaluation Game
Authors: Kulczycki Emanuel
Published: April 2023

Scientific research is communicated, organized, financed, governed, and evaluated through the process of publication. The result of this process is a highly competitive academic environment that rewards researchers for high volume publication, preferably in high-impact journals, leading to the popularised expression 'publish or perish'. Universities and other scientific institutions are under similar pressure, with their aggregated research output being under constant scrutiny. This innovative text provides a detailed introduction to the origin and development of the scholarly metrics used to measure academic productivity, and the effect they have upon the quality and diversity of scientific research. With its careful attention to both the positive and negative outcomes of research evaluation and their distinct expressions around the globe, The Evaluation Game guides the way to a more grounded understanding of metrics, and the diverse academic cultures they give rise to.
Slavery, Freedom Suits, and Legal Praxis in the Ottoman Empire, ca. 1590–1710
Authors: White Joshua M.
Published: April 2023

Beginning with the story of the Muslim youth Mehmed bin Abdülcelil of Tunis, this article examines the plight of Ottoman subjects abducted and sold into slavery within the Ottoman Empire and their efforts to regain freedom through Ottoman courts. Freedom suits (hürriyet davaları) were common in the seventeenth-century Ottoman Empire, so much so that contemporary legal praxis manuals (sukuk) always provided examples of how to document them, but they have never been systematically studied for this period in which slave ownership was extremely widespread and the legality of enslavement depended solely on religion and subjecthood. Drawing on a sample of seventy-nine suits from greater Istanbul and elevensukukmanuscripts, this article considers how the trade in the illegally enslaved was concealed by the immense traffic in licit captives and how the theoretical protections of Ottoman subjecthood clashed with the practical challenges of how to prove it, exposing the gap between slavery as legal institution and slaving in practice. Whereas the vast majority of freedom suits ended in rulings in favor of the victims, most of the illegally enslaved probably never managed to have their cases heard or were turned away for lack of evidence.
Frequency comb MIMO OFDM radar demonstrator with high unambiguous velocity
Authors: Nuss Benjamin , Giroto de Oliveira Lucas , Zwick Thomas
Published: April 2023

Digital radar waveforms such as orthogonal frequency-division multiplexing (OFDM) often have the disadvantage that they require high sampling rates if fine range resolutions have to be achieved. The frequency comb OFDM radar scheme offers a possibility to overcome this drawback and to improve the range resolution without increasing the sampling rate. Simultaneously, the high unambiguous velocity, which is one of the advantages of digital radar waveforms, is retained and due to the simple generation of orthogonal transmit signals, it is well suited for multiple-input multiple-output (MIMO) applications. To prove all these features of the frequency comb OFDM radar scheme, a suitable 4 × 4 MIMO demonstrator including frequency comb generation as well as up- and downconversion with these combs has been set up. Its functionality has been validated with real measurements in an anechoic chamber in conjunction with a radar target simulator to emulate very high velocities.
A four-port wideband filtering monopole MIMO array for sub-6 GHz 5G communications
Authors: Ayyappan Jasmine Vijithra , Mohammed Gulam Nabi Alsath , Subbaraj Sangeetha
Published: April 2023

This communication presents the significance of a four-port 2×2 multiple input multiple output antenna operating in mid-band frequency for 5G handheld device application. A microstrip-fed reference truncated decagonal monopole antenna operating at 3.9 GHz and a modified split-ring resonator (SRR)-based low-pass filter that excites at a cut-off frequency of 6.5 GHz are designed. On introducing a stub line in the SRR structure, the proposed filter shows a good out-of-band rejection beyond 6.5 GHz. By integrating the filter into the reference monopole, a wideband filtering monopole with improved stopband performance is obtained. A four-port MIMO array is constructed by orthogonally positioning the antenna with a center-to-center separation of 0.25λ0. To improve isolation, a pair of inverted L-stubs of varying lengths is introduced. The closed loop formed by the interconnection of stubs enhances isolation within the frequency range of 3–3.5 GHz. The fabricated prototype fosters an impedance bandwidth of 66.67%, isolation >18.5 dB, an average suppression of 15 dB, an average peak gain >3.7 dB, envelope correlation coefficient < 0.015, Actual Diversity Gain (ADG) > 9.9 dB, Effective Diversity Gain (EDG) > 8.8 dB, and efficiency >88%. The proposed design is suitable for 5G sub-6 GHz applications such as n48, n77, n78, n79 bands, WiMAX, and LTE bands 42, 43, 46, 47, 48.
Adverse Health Outcomes Following Hurricane Harvey: A Comparison of Remotely‐Sensed and Self‐Reported Flood Exposure Estimates
Authors: Ramesh Balaji , Callender Rashida , Zaitchik Benjamin F. , Jagger Meredith , Swarup Samarth , Gohlke Julia M.
Published: April 2023

Remotely sensed inundation may help to rapidly identify areas in need of aid during and following floods. Here we evaluate the utility of daily remotely sensed flood inundation measures and estimate their congruence with self‐reported home flooding and health outcomes collected via the Texas Flood Registry (TFR) following Hurricane Harvey. Daily flood inundation for 14 days following the landfall of Hurricane Harvey was acquired from FloodScan. Flood exposure, including number of days flooded and flood depth was assigned to geocoded home addresses of TFR respondents (N = 18,920 from 47 counties). Discordance between remotely‐sensed flooding and self‐reported home flooding was measured. Modified Poisson regression models were implemented to estimate risk ratios (RRs) for adverse health outcomes following flood exposure, controlling for potential individual level confounders. Respondents whose home was in a flooded area based on remotely‐sensed data were more likely to report injury (RR = 1.5, 95% CI: 1.27–1.77), concentration problems (1.36, 95% CI: 1.25–1.49), skin rash (1.31, 95% CI: 1.15–1.48), illness (1.29, 95% CI: 1.17–1.43), headaches (1.09, 95% CI: 1.03–1.16), and runny nose (1.07, 95% CI: 1.03–1.11) compared to respondents whose home was not flooded. Effect sizes were larger when exposure was estimated using respondent‐reported home flooding. Near‐real time remote sensing‐based flood products may help to prioritize areas in need of assistance when on the ground measures are not accessible.
Unprecedented Winter Rainfall Initiates Large Snow Avalanche and Mass Movement Cycle in New Zealand's Southern Alps/Kā Tiritiri o te Moana
Authors: Miller Aubrey D. , Redpath Todd A. N. , Sirguey Pascal , Cox Simon C. , Bartelt Perry , Bogie Don , Conway Jono P. , Cullen Nicolas J. , Bühler Yves
Published: April 2023

An exceptional July 2022 winter storm brought 550 mm of precipitation to the Southern Alps of New Zealand. A series of alpine mass movements occurred during the storm, including a widespread snow avalanche cycle, debris flows, and erosion from rain runoff. We detail the sequence of events in the Kitchener avalanche path. Here, two large snow avalanches were followed by a debris flow. Substantial erosion of deposition and the underlying alluvial fan were induced by runoff from over 300 mm of rain falling after the first avalanche. The Kitchener path saw the largest avalanche since 1986, testing the utility of a diversion berm constructed for a 1:100‐year event. Results from a unmanned aerial vehicle lidar survey and numerical modeling characterize the rain‐on‐snow hazard sequence. In particular, the rain‐on‐snow event occurred on a deep mid‐winter snowpack, offering insights into future hazards posed by increasingly frequent extreme alpine precipitation.
Water Table and Permeability Estimation From Multi‐Channel Seismoelectric Spectral Ratios
Authors: Hu Kaiyan , Ren Hengxin , Huang Qinghua , Zeng Ling , Butler Karl E. , Jougnot Damien , Linde Niklas , Holliger Klaus
Published: April 2023

Recent developments in predicting and interpreting seismoelectric (SE) signals suggest a great potential for studying near‐surface hydrogeological properties, particularly in the vadose zone. Previous studies have revealed that the SE spectral ratios obtained from earthquake‐triggered SE data contain valuable hydrogeological information concerning porous media (e.g., permeability, porosity, fluid viscosity, and salinity). This study introduces Multi‐Channel SeismoElectric Spectral Ratios (MC‐SESRs) by considering an active seismic source acting on the ground surface. The frequency‐ and saturation‐dependent excess charge density is adopted to calculate the cross‐coupling coefficients. Applying a supervised learning task based on a flat neural network, the so‐called “broad learning (BL)” model, to map and extract the features of MC‐SESRs data, we seek to determine the permeability and the water table depth. Our results indicate that (a) MC‐SESRs are sensitive to the water table depth and permeability; (b) using more traces of SESRs data for inversion can increase accuracy; and (c) the changing water table can be rapidly determined by the MC‐SESRs by resorting to the BL inverse model, and it can attain an excellent accuracy while disturbed by data noise and misspecified model parameters (e.g., porosity and permeability) with errors of up to 20%. The proposed MC‐SESRs inversion has potential applications for non‐invasive monitoring in shallow porous media (e.g., frost thawing and geothermal upwelling).
Late Oligocene Formation of the Pearl River Triggered by the Opening of the South China Sea
Authors: Zhang Zengjie , Daly J. Stephen , Tian Yuntao , Lei Chao , Sun Xilin , Badenszki Eszter , Qin Yonghui , Hu Jie
Published: April 2023

The Pearl River is one of the largest rivers entering the South China Sea, yet its initiation time remains debated, a topic we address using Pb isotopes in detrital K‐feldspar. Based on these Pb data, Eocene and Early Oligocene sandstones from the northern South China Sea are interpreted to have been supplied with sediment by proximal rivers draining the Cathaysia Block. In contrast, the Late Oligocene and Miocene sandstones are mainly derived from the western Pearl tributaries (e.g., Hongshui River), suggesting that the Pearl River had formed by the Late Oligocene. Detrital zircon data from the Beibuwan Basin previously suggested that the western tributaries flowed into this basin before being captured by the paleo‐Pearl River. These lines of evidence suggest that progressive headward erosion of the eastern Pearl River and late Oligocene integration of this large fluvial system can be linked to contemporaneous sea‐floor spreading of the South China Sea.
A Linear Velocity Gradient in the Subsolar Magnetosheath
Authors: Silveira M. V. D. , Sibeck D. G.
Published: April 2023

Tracking the location and motion of the bow shock and magnetopause can reveal many aspects concerning the nature of the solar wind‐magnetosphere interaction. In the absence of missions that image the magnetopause, we propose to detect and track the magnetopause and bow shock motion using multipoint in situ observations of the magnetosheath. Making theoretical assumptions corroborated by numerical simulations, Sibeck et al. (2022, https://doi.org/10.1029/2022JA030704) proposed a method to predict the subsolar magnetopause and the bow shock from the linear variation in magnetosheath plasma velocity expected from global magnetohydrodynamic simulations along the Sun‐Earth line. This paper presents a case study that employs the velocity gradient method using multi‐point THEMIS plasma observations from 21 to 22 June 2007. Using the five THEMIS spacecraft we demonstrate that the radial gradient in plasma velocity remains nearly linear across the subsolar magnetosheath, except when the magnetosheath lies behind the quasi‐parallel bow shock and conditions are very turbulent. The bow shock and magnetopause move outward in response to a gradual decrease in solar wind dynamic pressure. We show that results from the velocity gradient method agree well with predictions of global magnetohydrodynamic and empirical models for this time interval. The velocity gradient method can therefore be used to remotely determine the location of the magnetopause and bow shock, solely based on two‐spacecraft measurements at the subsolar magnetosheath when not downstream of the quasi‐parallel shock.
Sugar-sweetened beverages, low/no-calorie beverages, fruit juice and non-alcoholic fatty liver disease defined by fatty liver index: the SWEET project
Authors: Naomi Novita D. , Ngo Joy , Brouwer-Brolsma Elske M. , Buso Marion E. C. , Soedamah-Muthu Sabita S. , Pérez-Rodrigo Carmen , Harrold Joanne A. , Halford Jason C. G. , Raben Anne , Geleijnse Johanna M. , Serra-Majem Lluis , Feskens Edith J. M.
Published: April 2023

Abstract

Background

Sweetened beverage intake may play a role in non-alcoholic fatty liver disease (NAFLD) development, but scientific evidence on their role is limited. This study examined associations between sugar-sweetened beverages (SSB), low/no-calorie beverages (LNCB) and fruit juice (FJ) intakes and NAFLD in four European studies.

Methods

Data for 42,024 participants of Lifelines Cohort, NQPlus, PREDIMED-Plus and Alpha Omega Cohort were cross-sectionally analysed. NAFLD was assessed using Fatty Liver Index (FLI) (≥60). Restricted cubic spline analyses were used to visualize dose–response associations in Lifelines Cohort. Cox proportional hazard regression analyses with robust variance were performed for associations in individual cohorts; data were pooled using random effects meta-analysis. Models were adjusted for demographic, lifestyle, and other dietary factors.

Results

Each additional serving of SSB per day was associated with a 7% higher FLI-defined NAFLD prevalence (95%CI 1.03–1.11). For LNCB, restricted cubic spline analysis showed a nonlinear association with FLI-defined NAFLD, with the association getting stronger when consuming ≤1 serving/day and levelling off at higher intake levels. Pooled Cox analysis showed that intake of >2 LNCB servings/week was positively associated with FLI-defined NAFLD (PR 1.38, 95% CI 1.15–1.61; reference: non-consumers). An inverse association was observed for FJ intake of ≤2 servings/week (PR 0.92, 95% CI: 0.88–0.97; reference: non-consumers), but not at higher intake levels. Theoretical replacement of SSB with FJ showed no significant association with FLI-defined NAFLD prevalence (PR 0.97, 95% CI 0.95–1.00), whereas an adverse association was observed when SSB was replaced with LNCB (PR 1.12, 95% CI 1.03–1.21).

Conclusions

Pooling results of this study showed that SSB and LNCB were positively associated with FLI-defined NAFLD prevalence. Theoretical replacement of SSB with LNCB was associated with higher FLI-defined NAFLD prevalence. An inverse association was observed between moderate intake of FJ and FLI-defined NAFLD. Our results should be interpreted with caution as reverse causality cannot be ruled out.
Effects of cannabidiol on anandamide levels in individuals with cannabis use disorder: findings from a randomised clinical trial for the treatment of cannabis use disorder
Authors: Hua Daniel Ying-Heng , Hindocha Chandni , Baio Gianluca , Lees Rachel , Shaban Natacha , Morgan Celia J. , Mofeez Ali , Curran H. Valerie , Freeman Tom P.
Published: April 2023

Cannabidiol (CBD) has shown promise in treating psychiatric disorders, including cannabis use disorder – a major public health burden with no approved pharmacotherapies. However, the mechanisms through which CBD acts are poorly understood. One potential mechanism of CBD is increasing levels of anandamide, which has been implicated in psychiatric disorders including depression and cannabis use disorder. However, there is a lack of placebo-controlled human trials investigating this in psychiatric disorders. We therefore assessed whether CBD affects plasma anandamide levels compared to placebo, within a randomised clinical trial of CBD for the treatment of cannabis use disorder. Individuals meeting criteria for cannabis use disorder and attempting cannabis cessation were randomised to 28-day administration with placebo (n = 23), 400 mg CBD/day (n = 24) or 800 mg CBD/day (n = 23). We estimated the effects of each CBD dose compared to placebo on anandamide levels from baseline to day 28. Analyses were conducted both unadjusted and adjusted for cannabis use during the trial to account for effects of cannabis on the endocannabinoid system. We also investigated whether changes in plasma anandamide levels were associated with clinical outcomes relevant for cannabis use disorder (cannabis use, withdrawal, anxiety, depression). There was an effect of 800 mg CBD compared to placebo on anandamide levels from baseline to day 28 after adjusting for cannabis use. Pairwise comparisons indicated that anandamide levels unexpectedly reduced from baseline to day 28 in the placebo group (−0.048, 95% CI [−0.089, −0.007]), but did not change in the 800 mg CBD group (0.005, 95% CI [−0.036, 0.047]). There was no evidence for an effect of 400 mg CBD compared to placebo. Changes in anandamide levels were not associated with clinical outcomes. In conclusion, this study found preliminary evidence that 28-day treatment with CBD modulates anandamide levels in individuals with cannabis use disorder at doses of 800 mg/day but not 400 mg/day compared to placebo.
Bone serves as a transfer station for secondary dissemination of breast cancer
Authors: Huang Yufan , Wang Hongli , Yue Xiaomin , Li Xiaoqing
Published: April 2023

Metastasis is responsible for the majority of deaths among breast cancer patients. Although parallel polyclonal seeding has been shown to contribute to organ-specific metastasis, in the past decade, horizontal cross-metastatic seeding (metastasis-to-metastasis spreading) has also been demonstrated as a pattern of distant metastasis to multiple sites. Bone, as the most frequent first destination of breast cancer metastasis, has been demonstrated to facilitate the secondary dissemination of breast cancer cells. In this review, we summarize the clinical and experimental evidence that bone is a transfer station for the secondary dissemination of breast cancer. We also discuss the regulatory mechanisms of the bone microenvironment in secondary seeding of breast cancer, focusing on stemness regulation, quiescence-proliferation equilibrium regulation, epigenetic reprogramming and immune escape of cancer cells. Furthermore, we highlight future research perspectives and strategies for preventing secondary dissemination from bone.
Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts
Authors: Piñeiro-Hermida Sergio , Bosso Giuseppe , Sánchez-Vázquez Raúl , Martínez Paula , Blasco Maria A.
Published: April 2023

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8+ T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.
Environmental context-dependent activation of dopamine neurons via putative amygdala-nigra pathway in macaques
Authors: Maeda Kazutaka , Inoue Ken-ichi , Takada Masahiko , Hikosaka Okihide
Published: April 2023

Seeking out good and avoiding bad objects is critical for survival. In practice, objects are rarely good every time or everywhere, but only at the right time or place. Whereas the basal ganglia (BG) are known to mediate goal-directed behavior, for example, saccades to rewarding objects, it remains unclear how such simple behaviors are rendered contingent on higher-order factors, including environmental context. Here we show that amygdala neurons are sensitive to environments and may regulate putative dopamine (DA) neurons via an inhibitory projection to the substantia nigra (SN). In male macaques, we combined optogenetics with multi-channel recording to demonstrate that rewarding environments induce tonic firing changes in DA neurons as well as phasic responses to rewarding events. These responses may be mediated by disinhibition via a GABAergic projection onto DA neurons, which in turn is suppressed by an inhibitory projection from the amygdala. Thus, the amygdala may provide an additional source of learning to BG circuits, namely contingencies imposed by the environment.
Observing and braiding topological Majorana modes on programmable quantum simulators
Authors: Harle Nikhil , Shtanko Oles , Movassagh Ramis
Published: April 2023

Electrons are indivisible elementary particles, yet paradoxically a collection of them can act as a fraction of a single electron, exhibiting exotic and useful properties. One such collective excitation, known as a topological Majorana mode, is naturally stable against perturbations, such as unwanted local noise, and can thereby robustly store quantum information. As such, Majorana modes serve as the basic primitive of topological quantum computing, providing resilience to errors. However, their demonstration on quantum hardware has remained elusive. Here, we demonstrate a verifiable identification and braiding of topological Majorana modes using a superconducting quantum processor as a quantum simulator. By simulating fermions on a one-dimensional lattice subject to a periodic drive, we confirm the existence of Majorana modes localized at the edges, and distinguish them from other trivial modes. To simulate a basic logical operation of topological quantum computing known as braiding, we propose a non-adiabatic technique, whose implementation reveals correct braiding statistics in our experiments. This work could further be used to study topological models of matter using circuit-based simulations, and shows that long-sought quantum phenomena can be realized by anyone in cloud-run quantum simulations, whereby accelerating fundamental discoveries in quantum science and technology.
Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6
Authors: Taha Taha Y. , Chen Irene P. , Hayashi Jennifer M. , Tabata Takako , Walcott Keith , Kimmerly Gabriella R. , Syed Abdullah M. , Ciling Alison , Suryawanshi Rahul K. , Martin Hannah S. , Bach Bryan H. , Tsou Chia-Lin , Montano Mauricio , Khalid Mir M. , Sreekumar Bharath K. , Renuka Kumar G. , Wyman Stacia , Doudna Jennifer A. , Ott Melanie
Published: April 2023

Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.
Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
Authors: Maroto Irene B. , Costas-Insua Carlos , Berthoux Coralie , Moreno Estefanía , Ruiz-Calvo Andrea , Montero-Fernández Carlos , Macías-Camero Andrea , Martín Ricardo , García-Font Nuria , Sánchez-Prieto José , Marsicano Giovanni , Bellocchio Luigi , Canela Enric I. , Casadó Vicent , Galve-Roperh Ismael , Núñez Ángel , Fernández de Sevilla David , Rodríguez-Crespo Ignacio , Castillo Pablo E. , Guzmán Manuel
Published: April 2023

The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that theC-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.
High throughput calculations for a dataset of bilayer materials
Authors: Barik Ranjan Kumar , Woods Lilia M.
Published: April 2023

Bilayer materials made of 2D monolayers are emerging as new systems creating diverse opportunities for basic research and applications in optoelectronics, thermoelectrics, and topological science among others. Herein, we present a computational bilayer materials dataset containing 760 structures with their structural, electronic, and transport properties. Different stacking patterns of each bilayer have been framed by analyzing their monolayer symmetries. Density functional theory calculations including van der Waals interactions are carried out for each stacking pattern to evaluate the corresponding ground states, which are correctly identified for experimentally synthesized transition metal dichalcogenides, graphene, boron nitride, and silicene. Binding energies and interlayer charge transfer are evaluated to analyze the interlayer coupling strength. Our dataset can be used for materials screening and data-assisted modeling for desired thermoelectric or optoelectronic applications.
CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer
Authors: Guo Nancy , Yang Aijun , Farooq Fabiha Binte , Kalaria Shreena , Moss Elena , DeVorkin Lindsay , Lesperance Mary , Bénard François , Wilson Don , Tinker Anna V. , Nathoo Farouk S. , Hamilton Phineas T. , Lum Julian J.
Published: April 2023

Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [18F]EF5-PET/CT imaging, transcriptome profiling, and spatially-resolved histological analysis to evaluate relationships between CAIX, CD8, and survival in CCOC. Tissue microarrays (TMAs) were evaluated for 218 cases in the Canadian COEUR study. Non-spatial relationships between CAIX and CD8 were investigated using Spearman rank correlation, negative binomial regression and gene set enrichment analysis. Spatial relationships at the cell level were investigated using the cross K-function. Survival analysis was used to assess the relationship of CAIX and CD8 with patient survival for 154 cases. CD8 + T cell infiltration positively predicted survival with estimated hazard ratio 0.974 (95% CI 0.950, 1000). The negative binomial regression analysis found a strong TMA effect (p-value < 0.0001). It also indicated a negative association between CD8 and CAIX overall (p-value = 0.0171) and in stroma (p-value = 0.0050) but not in tumor (p-value = 0.173). Examination of the spatial association between the locations of CD8 + T cells and CAIX cells found a significant amount of heterogeneity in the first TMA, while in the second TMA there was a clear signal indicating negative spatial association in stromal regions. These results suggest that hypoxia may contribute to immune exclusion, primarily mediated by effects in stroma.
Hypnotic suggestions cognitively penetrate tactile perception through top-down modulation of semantic contents
Authors: Markmann Marius , Lenz Melanie , Höffken Oliver , Steponavičiūtė Agnė , Brüne Martin , Tegenthoff Martin , Dinse Hubert R. , Newen Albert
Published: April 2023

Perception is subject to ongoing alterations by learning and top-down influences. Although abundant studies have shown modulation of perception by attention, motivation, content and context, there is an unresolved controversy whether these examples provide true evidence that perception is penetrable by cognition. Here we show that tactile perception assessed as spatial discrimination can be instantaneously and systematically altered merely by the semantic content during hypnotic suggestions. To study neurophysiological correlates, we recorded EEG and SEPs. We found that the suggestion “your index finger becomes bigger” led to improved tactile discrimination, while the suggestion “your index finger becomes smaller” led to impaired discrimination. A hypnosis without semantic suggestions had no effect but caused a reduction of phase-locking synchronization of the beta frequency band between medial frontal cortex and the finger representation in somatosensory cortex. Late SEP components (P80–N140 complex) implicated in attentional processes were altered by the semantic contents, but processing of afferent inputs in SI remained unaltered. These data provide evidence that the psychophysically observed modifiability of tactile perception by semantic contents is not simply due to altered perception-based judgments, but instead is a consequence of modified perceptual processes which change the perceptual experience.
Layout of ancient Greek papyri through lead-drawn ruling lines revealed by Macro X-Ray Fluorescence Imaging
Authors: Romano Francesco P. , Puglia Enzo , Caliri Claudia , Pavone Danilo P. , Alessandrelli Michele , Busacca Andrea , Fatuzzo Claudia G. , Fleischer Kilian J. , Pernigotti Carlo , Preisler Zdenek , Vassallo Christian , Verhasselt Gertjan , Miliani Costanza , Ranocchia Graziano
Published: April 2023

The use of lead-drawn ruling lines by ancient scribes for the layout of Greek papyrus rolls was known to us only from classical authors and was postulated by a few scholars in modern times. In situ application of noninvasive Macro X-Ray Fluorescence Imaging Spectroscopy (MA-XRF) to unrolled papyri from Herculaneum, dating from about 200 BC to the 1st century AD, has provided the first direct evidence of such practice in ancient book production. The key experimental proof of periodic lines drawn in lead was gathered by a highly sensitive MA-XRF mobile instrument, which allowed detection of ultra-low trace residues of metals with detection limits that rival synchrotron light instruments. Elemental distribution maps of Pb have revealed three different systems of textual layout in ancient papyrus rolls and have resolved the dispute around so-called Maas’ Law, by delivering experimental proof that slanted text columns were a deliberate aesthetic choice of scribes.
Various effects of 11,12 EET rescue wound healing in a combined model of diabetes and ischemia
Authors: Sommer Katharina , Jakob Heike , Lettenmeier Theresa , Henrich Dirk , Sterz Jasmina , Marzi Ingo , Frank Johannes
Published: April 2023

Chronic non healing wounds in diabetic patients still impose a major problem in modern medicine. Especially additional peripheral vascular disease complicates treatment success in these patients. Thus, we analyzed the effects of 11,12 epoxyeicosatrienoic acid (EET) in a combined model of hyperglycemia and ischemia in mice. Hyperglycemia was induced by Streptozotozin 2 weeks prior to wounding. 3 days before wound creation 2 of the 3 suppling vessels of the moue ear were cautherized for ischemia. Either 11,12 EET or solvent for control was applied. Wound closure as well as TNF-α, TGF-β, SDF-1α, VEGF, CD31, and Ki67 were measured. The wounds closed on day 14.4 ± 0.4 standard deviation (SD). 11,12 EET treatment enhanced healing to 9.8 ± 0.6 SD. TNF-α level was augmented on day 9 compared to control and receded on day 18. TGF-β seemed to be elevated all days observed after 11,12 EET treatment. SDF-1α was enhanced on day 6 and 9 by 11,12 EET, and VEGF on day 6 and 18 as well as CD13 on day 3, 6, and 18. 11,12 EET did not alter Ki67. 11,12 EET are able to rescue deteriorated wound healing in a combined model of hyperglycamia and ischemia by resolution of inflammation, augmentation of neovascularization and increasing expression of TGF-β as well as SDF-1α.
The effects of large roughness elements on the in-stream transport and retention of polystyrene microplastics
Authors: Ijaz Usama , Baki Abul B. M. , Abdul-Aziz Omar I. , Zhang Wenming , Christian Alan D.
Published: April 2023

The mechanisms controlling transport and retention of microplastics (MPs) in riverine systems are not understood well. We investigated the impact of large roughness elements (LREs) on in-stream transport and retention of the ubiquitous polystyrene-microplastics (PS-MPs). Scaled experiments were conducted with and without LREs under various shear Reynolds numbers (Re*) in an ecohydraulics flume. Our results, for the first time, demonstrated a clear dependence of the MPs’ velocity on Re* in LREs-dominated channel. Two distinct regimes and thresholds were identified: lower Re* (≤ 15,000) regime corresponding to higher velocities of MPs ($${U}_{MPs}^{*}$$

U

MPs

∗

> 0.45), and higher Re* (> 15,000) to lower $${U}_{MPs}^{*} ($$

U

MPs

∗

(

< 0.45). The presence and higher density of LREs increased Re*, decreased $${U}_{MPs}^{*}$$

U

MPs

∗

, and enhanced the PS-MPs capture. The LREs-generated turbulence kinetic energy (TKE) was found to be a good predictor of PS-MPs transport and retention rates, indicating the effectiveness of LREs in retaining PS-MPs in streams and rivers.
Cortical glia in SOD1(G93A) mice are subtly affected by ALS-like pathology
Authors: Filipi Tereza , Matusova Zuzana , Abaffy Pavel , Vanatko Ondrej , Tureckova Jana , Benesova Sarka , Kubiskova Monika , Kirdajova Denisa , Zahumensky Jakub , Valihrach Lukas , Anderova Miroslava
Published: April 2023

The role of glia in amyotrophic lateral sclerosis (ALS) is undeniable. Their disease-related activity has been extensively studied in the spinal cord, but only partly in the brain. We present herein a comprehensive study of glia in the cortex of SOD1(G93A) mice—a widely used model of ALS. Using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, we inspected astrocytes, microglia, and oligodendrocytes, in four stages of the disease, respecting the factor of sex. We report minimal changes of glia throughout the disease progression and regardless of sex. Pseudobulk and single-cell analyses revealed subtle disease-related transcriptional alterations at the end-stage in microglia and oligodendrocytes, which were supported by immunohistochemistry. Therefore, our data support the hypothesis that the SOD1(G93A) mouse cortex does not recapitulate the disease in patients, and we recommend the use of a different model for future studies of the cortical ALS pathology.
First designing of a silicene-based optical MOSFET with outstanding performance
Authors: Emami-Nejad Hamed , mir Ali , Lorestaniweiss Zeinab , Farmani Ali , Talebzadeh Reza
Published: April 2023

Miniaturized integrated optical devices with low power consumption have long been considered hot candidates for plasmonic applications. While 2D materials such as graphene have been proposed for this purpose, they suffer from large propagation loss and low controllability at room temperature. Here, a silicene-based optical MOSFET with excellent performance is designed to achieve integrated circuit optical technology. The designed device is comprised of a silicene optical waveguide whose switching operation is performed by a gate and has a structure similar to an enhancement MOSFET with a formed channel. Unlike graphene, the surface conductivity of silicene can be controlled by both chemical potential and an electric field perpendicular to its surface. This unique feature of silicene is used to design and simulate an optical-MOSFET with transverse electric polarization at 300 K. The salient characteristics of the optical device include its nanoscale dimensions, ultra-low insertion loss of 0.13 dB, infinite extinction ratio, and quality factor of 688, proposing it as a promising tool for optical integration.
A comprehensive diagnostic approach in suspected neurosarcoidosis
Authors: Berntsson Shala Ghaderi , Elmgren Andreas , Gudjonsson Olafur , Grabowska Anna , Landtblom Anne-Marie , Moraes-Fontes Maria-Francisca
Published: April 2023

Neurosarcoidosis presents a diagnostic challenge in clinical settings, as it has no pathognomonic symptoms or signs and a wide range of differential diagnoses. The aim of this report is to present the pathological features of our group of patients, obtained through a systematic diagnostic approach. This retrospective cohort study enrolled all adult patients primarily diagnosed with neurosarcoidosis at the neurology department of a tertiary center in Sweden over a period of 30 years, from 1990 to 2021. We identified 90 patients, 54 with possible neurosarcoidosis and 36 with probable neurosarcoidosis. CNS biopsy revealed an alternative diagnosis for 24 patients, who were then excluded. The collected data from medical records included demographic and clinical characteristics, systemic and/or neurological isolated involvement, various laboratory tests, including cerebrospinal fluid (CSF), serum analysis, imaging studies (MRI, FDG-PET/CT, and HRCT), nerve conduction studies, electromyography, and pathology reports of central nervous system (CNS), and extra-neural tissue biopsies. Sixty-six patients were included in our cohort. The median age at onset of symptoms was 49 years, with a similar sex distribution. Cranial neuropathies (38%), motor deficit (32%), headache (16%), and pituitary dysfunction (12%) were the most common presenting features. CSF studies were abnormal in 77% of the patients, who showed lymphocytosis (57%), elevated protein (44%), oligoclonal bands (40%), elevated ACE (28%), and raised T lymphocyte CD4+/CD8+ ratios (13%). Strikingly, MRI showed that 17% of the patients presented with isolated pituitary gland lesions. FDG-PET/CT was performed in 22 patients (33%) and confirmed systemic sarcoidosis in 11. Despite our extensive workup, the final classification for our patients only allowed for a definite diagnosis in 14 patients; the remainder were classified as probable (32) or possible (20) neurosarcoidosis. Since 2007, the employment of a structured laboratory and imaging approach and the increasing number of CNS biopsies have facilitated and improved the process of correct attribution in patients with presumptive neurosarcoidosis, especially in patients with isolated neurological lesions. We highlight a higher frequency of pituitary lesions due to neurosarcoidosis than has been classically described. A detailed laboratory diagnostic workup is included.