bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors
Authors: Tsimberidou Apostolia Maria , Verschraegen Claire F. , Wesolowski Robert , Shia Chi-Sheng , Hsu Pei , Pearce Tillman E.
Published: May 2023

Background

Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264).

Methods

A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (days 1 and 8 of a 21-day cycle, Schedule A) or 8, 10, 12, or 14 mg/m2 (day 1 of a 21-day cycle, Schedule B).

Results

Dose-limiting hematologic toxicities at 12 mg/m2 in Schedule A led to dose and schedule modifications (Schedule B). In Schedule B, maximum tolerated dose was not reached at the maximum dose tested (14 mg/m2). Grade ≥3 anemia was noted in 3/6 patients treated at 14 mg/m2; the RP2D was 12 mg/m2 (Schedule B). Grade ≥3 treatment-emergent adverse events were experienced by 19/39 (49%) and included anemia (41%) and thrombocytopenia (26%); three patients experienced serious treatment-emergent adverse events (grade ≥3 anemia and thrombocytopenia). One patient had a partial response and 21/33 (64%) had stable disease.

Conclusions

The RP2D is 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.
Clinical-grade human umbilical cord-derived mesenchymal stem cells improved skeletal muscle dysfunction in age-associated sarcopenia mice
Authors: Wang Chao , Zhao Bichun , Zhai Jinglei , Wang Ailin , Cao Ning , Liao Tuling , Su Ruyu , He Lijuan , Li Yanhua , Pei Xuetao , Jia Yali , Yue Wen
Published: May 2023

With the expansion of the aging population, age-associated sarcopenia (AAS) has become a severe clinical disease of the elderly and a key challenge for healthy aging. Regrettably, no approved therapies currently exist for treating AAS. In this study, clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were administrated to two classic mouse models (SAMP8 mice and D-galactose-induced aging mice), and their effects on skeletal muscle mass and function were investigated by behavioral tests, immunostaining, and western blotting. Core data results showed that hUC-MSCs significantly restored skeletal muscle strength and performance in both mouse models via mechanisms including raising the expression of crucial extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging. For the first time, the study comprehensively evaluates and demonstrates the preclinical efficacy of clinical-grade hUC-MSCs for AAS in two mouse models, which not only provides a novel model for AAS, but also highlights a promising strategy to improve and treat AAS and other age-associated muscle diseases.
Revisiting the role of mesenchymal stem cells in tuberculosis and other infectious diseases
Authors: Devi Annu , Pahuja Isha , Singh Shashi Prakash , Verma Akanksha , Bhattacharya Debapriya , Bhaskar Ashima , Dwivedi Ved Prakash , Das Gobardhan
Published: May 2023

Mesenchymal stem cells (MSCs) play diverse roles ranging from regeneration and wound healing to immune signaling. Recent investigations have indicated the crucial role of these multipotent stem cells in regulating various aspects of the immune system. MSCs express unique signaling molecules and secrete various soluble factors that play critical roles in modulating and shaping immune responses, and in some other cases, MSCs can also exert direct antimicrobial effects, thereby helping with the eradication of invading organisms. Recently, it has been demonstrated that MSCs are recruited at the periphery of the granuloma containing Mycobacterium tuberculosis and exert “Janus”-like functions by harboring pathogens and mediating host protective immune responses. This leads to the establishment of a dynamic balance between the host and the pathogen. MSCs function through various immunomodulatory factors such as nitric oxide (NO), IDO, and immunosuppressive cytokines. Recently, our group has shown that M.tb uses MSCs as a niche to evade host protective immune surveillance mechanisms and establish dormancy. MSCs also express a large number of ABC efflux pumps; therefore, dormant M.tb residing in MSCs are exposed to a suboptimal dose of drugs. Therefore, it is highly likely that drug resistance is coupled with dormancy and originates within MSCs. In this review, we discussed various immunomodulatory properties of MSCs, their interactions with important immune cells, and soluble factors. We also discussed the possible roles of MSCs in the outcome of multiple infections and in shaping the immune system, which may provide insight into therapeutic approaches using these cells in different infection models.
Molecular basis for recognition and deubiquitination of 40S ribosomes by Otu2
Authors: Ikeuchi Ken , Ivic Nives , Buschauer Robert , Cheng Jingdong , Fröhlich Thomas , Matsuo Yoshitaka , Berninghausen Otto , Inada Toshifumi , Becker Thomas , Beckmann Roland
Published: May 2023

In actively translating 80S ribosomes the ribosomal protein eS7 of the 40S subunit is monoubiquitinated by the E3 ligase Not4 and deubiquitinated by Otu2 upon ribosomal subunit recycling. Despite its importance for translation efficiency the exact role and structural basis for this translational reset is poorly understood. Here, structural analysis by cryo-electron microscopy of native and reconstituted Otu2-bound ribosomal complexes reveals that Otu2 engages 40S subunits mainly between ribosome recycling and initiation stages. Otu2 binds to several sites on the intersubunit surface of the 40S that are not occupied by any other 40S-binding factors. This binding mode explains the discrimination against 80S ribosomes via the largely helical N-terminal domain of Otu2 as well as the specificity for mono-ubiquitinated eS7 on 40S. Collectively, this study reveals mechanistic insights into the Otu2-driven deubiquitination steps for translational reset during ribosome recycling/(re)initiation.
Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
Authors: Pagadala Meghana , Sears Timothy J. , Wu Victoria H. , Pérez-Guijarro Eva , Kim Hyo , Castro Andrea , Talwar James V. , Gonzalez-Colin Cristian , Cao Steven , Schmiedel Benjamin J. , Goudarzi Shervin , Kirani Divya , Au Jessica , Zhang Tongwu , Landi Teresa , Salem Rany M. , Morris Gerald P. , Harismendy Olivier , Patel Sandip Pravin , Alexandrov Ludmil B. , Mesirov Jill P. , Zanetti Maurizio , Day Chi-Ping , Fan Chun Chieh , Thompson Wesley K. , Merlino Glenn , Gutkind J. Silvio , Vijayanand Pandurangan , Carter Hannah
Published: May 2023

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibitCTSS, a gene implicated by cancer risk and ICB response-associated polygenic models;CTSSinhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.
Magnetic excitations beyond the single- and double-magnons
Authors: Elnaggar Hebatalla , Nag Abhishek , Haverkort Maurits W. , Garcia-Fernandez Mirian , Walters Andrew , Wang Ru-Pan , Zhou Ke-Jin , de Groot Frank
Published: May 2023

A photon carrying one unit of angular momentum can change the spin angular momentum of a magnetic system with one unit (ΔMs = ±1) at most. This implies that a two-photon scattering process can manipulate the spin angular momentum of the magnetic system with a maximum of two units. Herein we describe a triple-magnon excitation in α-Fe2O3, which contradicts this conventional wisdom that only 1- and 2-magnon excitations are possible in a resonant inelastic X-ray scattering experiment. We observe an excitation at exactly three times the magnon energy, along with additional excitations at four and five times the magnon energy, suggesting quadruple and quintuple-magnons as well. Guided by theoretical calculations, we reveal how a two-photon scattering process can create exotic higher-rank magnons and the relevance of these quasiparticles for magnon-based applications.
Upscaled production of an ultramicroporous anion-exchange membrane enables long-term operation in electrochemical energy devices
Authors: Song Wanjie , Peng Kang , Xu Wei , Liu Xiang , Zhang Huaqing , Liang Xian , Ye Bangjiao , Zhang Hongjun , Yang Zhengjin , Wu Liang , Ge Xiaolin , Xu Tongwen
Published: May 2023

The lack of high-performance and substantial supply of anion-exchange membranes is a major obstacle to future deployment of relevant electrochemical energy devices. Here, we select two isomers (m-terphenyl and p-terphenyl) and balance their ratio to prepare anion-exchange membranes with well-connected and uniformly-distributed ultramicropores based on robust chemical structures. The anion-exchange membranes display high ion-conducting, excellent barrier properties, and stability exceeding 8000 h at 80 °C in alkali. The assembled anion-exchange membranes present a desirable combination of performance and durability in several electrochemical energy storage devices: neutral aqueous organic redox flow batteries (energy efficiency of 77.2% at 100 mA cm−2, with negligible permeation of redox-active molecules over 1100 h), water electrolysis (current density of 5.4 A cm−2at 1.8 V, 90 °C, with durability over 3000 h), and fuel cells (power density of 1.61 W cm−2under a catalyst loading of 0.2 mg cm−2, with open-circuit voltage durability test over 1000 h). As a demonstration of upscaled production, the anion-exchange membranes achieve roll-to-roll manufacturing with a width greater than 1000 mm.
Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease
Authors: Huang Zhi , Merrihew Gennifer E. , Larson Eric B. , Park Jea , Plubell Deanna , Fox Edward J. , Montine Kathleen S. , Latimer Caitlin S. , Dirk Keene C. , Zou James Y. , MacCoss Michael J. , Montine Thomas J.
Published: May 2023

Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.
High-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq
Authors: Xu Ziye , Zhang Tianyu , Chen Hongyu , Zhu Yuyi , Lv Yuexiao , Zhang Shunji , Chen Jiaye , Chen Haide , Yang Lili , Jiang Weiqin , Ni Shengyu , Lu Fangru , Wang Zhaolun , Yang Hao , Dong Ling , Chen Feng , Zhang Hong , Chen Yu , Liu Jiong , Zhang Dandan , Fan Longjiang , Guo Guoji , Wang Yongcheng
Published: May 2023

Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank for clinical history and follow-up data. It is still challenging to achieve single cell/nucleus RNA (sc/snRNA) profile in FFPE tissues. Here, we develop a droplet-based snRNA sequencing technology (snRandom-seq) for FFPE tissues by capturing full-length total RNAs with random primers. snRandom-seq shows a minor doublet rate (0.3%), a much higher RNA coverage, and detects more non-coding RNAs and nascent RNAs, compared with state-of-art high-throughput scRNA-seq technologies. snRandom-seq detects a median of >3000 genes per nucleus and identifies 25 typical cell types. Moreover, we apply snRandom-seq on a clinical FFPE human liver cancer specimen and reveal an interesting subpopulation of nuclei with high proliferative activity. Our method provides a powerful snRNA-seq platform for clinical FFPE specimens and promises enormous applications in biomedical research.
PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants
Authors: Muranen Taru A. , Morra Anna , Khan Sofia , Barnes Daniel R. , Bolla Manjeet K. , Dennis Joe , Keeman Renske , Leslie Goska , Parsons Michael T. , Wang Qin , Ahearn Thomas U. , Aittomäki Kristiina , Andrulis Irene L. , Arun Banu K. , Behrens Sabine , Bialkowska Katarzyna , Bojesen Stig E. , Camp Nicola J. , Chang-Claude Jenny , Czene Kamila , Devilee Peter ,   HEBON investigators, Domchek Susan M. , Dunning Alison M. , Engel Christoph , Evans D. Gareth , Gago-Dominguez Manuela , García-Closas Montserrat , Gerdes Anne-Marie , Glendon Gord , Guénel Pascal , Hahnen Eric , Hamann Ute , Hanson Helen , Hooning Maartje J. , Hoppe Reiner , Izatt Louise , Jakubowska Anna , James Paul A. , Kristensen Vessela N. , Lalloo Fiona , Lindeman Geoffrey J. , Mannermaa Arto , Margolin Sara , Neuhausen Susan L. , Newman William G. , Peterlongo Paolo , Phillips Kelly-Anne , Pujana Miquel Angel , Rantala Johanna , Rønlund Karina , Saloustros Emmanouil , Schmutzler Rita K. , Schneeweiss Andreas , Singer Christian F. , Suvanto Maija , Tan Yen Yen , Teixeira Manuel R. , Thomassen Mads , Tischkowitz Marc , Tripathi Vishakha , Wappenschmidt Barbara , Zhao Emily , Easton Douglas F. , Antoniou Antonis C. , Chenevix-Trench Georgia , Pharoah Paul D. P. , Schmidt Marjanka K. , Blomqvist Carl , Nevanlinna Heli
Published: May 2023

We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.
Vertex dominated superconductivity in intercalated FeSe
Authors: Acharya Swagata , Katsnelson Mikhail I. , van Schilfgaarde Mark
Published: May 2023

Bulk FeSe becomes superconducting below 9 K, but the critical temperature (Tc) is enhanced almost universally by a factor of ~4–5 when it is intercalated with alkali elements. How intercalation modifies the structure is known from in-situ X-ray and neutron scattering techniques, but why Tc changes so dramatically is not known. Here we show that there is one-to-one correspondence between the enhancement in magnetic instabilities at certain q vectors and superconducting pairing vertex, even while the nuclear spin relaxation rate 1/(T1T) may not reflect this enhancement. Intercalation modifies electronic screening both in the plane and also between layers. We disentangle quantitatively how superconducting pairing vertex gains from each such changes in electronic screening. Intercalated FeSe provides an archetypal example of superconductivity where information derived from the single-particle electronic structure appears to be insufficient to account for the origins of superconductivity, even when they are computed including correlation effects. We show that the five-fold enhancement in Tc on intercalation is not sensitive to the exact position of the dxy at Γ point, as long as it stays close to EF. Finally, we show that intercalation also significantly softens the collective charge excitations, suggesting the electron-phonon interaction could play some role in intercalated FeSe.
Global transmission suitability maps for dengue virus transmitted by Aedes aegypti from 1981 to 2019
Authors: Nakase Taishi , Giovanetti Marta , Obolski Uri , Lourenço José
Published: May 2023

Mosquito-borne viruses increasingly threaten human populations due to accelerating changes in climate, human and mosquito migration, and land use practices. Over the last three decades, the global distribution of dengue has rapidly expanded, causing detrimental health and economic problems in many areas of the world. To develop effective disease control measures and plan for future epidemics, there is an urgent need to map the current and future transmission potential of dengue across both endemic and emerging areas. Expanding and applying Index P, a previously developed mosquito-borne viral suitability measure, we map the global climate-driven transmission potential of dengue virus transmitted by Aedes aegypti mosquitoes from 1981 to 2019. This database of dengue transmission suitability maps and an R package for Index P estimations are offered to the public health community as resources towards the identification of past, current and future transmission hotspots. These resources and the studies they facilitate can contribute to the planning of disease control and prevention strategies, especially in areas where surveillance is unreliable or non-existent.
Discovery of two new isoforms of the human DUT gene
Authors: Rácz Gergely Attila , Nagy Nikolett , Várady György , Tóvári József , Apáti Ágota , Vértessy Beáta G.
Published: May 2023

In human cells two dUTPase isoforms have been described: one nuclear (DUT-N) and one mitochondrial (DUT-M), with cognate localization signals. In contrast, here we identified two additional isoforms; DUT-3 without any localization signal and DUT-4 with the same nuclear localization signal as DUT-N. Based on an RT-qPCR method for simultaneous isoform-specific quantification we analysed the relative expression patterns in 20 human cell lines of highly different origins. We found that the DUT-N isoform is expressed by far at the highest level, followed by the DUT-M and the DUT-3 isoform. A strong correlation between expression levels of DUT-M and DUT-3 suggests that these two isoforms may share the same promoter. We analysed the effect of serum starvation on the expression of dUTPase isoforms compared to non-treated cells and found that the mRNA levels of DUT-N decreased in A-549 and MDA-MB-231 cells, but not in HeLa cells. Surprisingly, upon serum starvation DUT-M and DUT-3 showed a significant increase in the expression, while the expression level of the DUT-4 isoform did not show any changes. Taken together our results indicate that the cellular dUTPase supply may also be provided in the cytoplasm and starvation stress induced expression changes are cell line dependent.
A smart approach to EMG envelope extraction and powerful denoising for human–machine interfaces
Authors: Esposito Daniele , Centracchio Jessica , Bifulco Paolo , Andreozzi Emilio
Published: May 2023

Electromyography (EMG) is widely used in human–machine interfaces (HMIs) to measure muscle contraction by computing the EMG envelope. However, EMG is largely affected by powerline interference and motion artifacts. Boards that directly provide EMG envelope, without denoising the raw signal, are often unreliable and hinder HMIs performance. Sophisticated filtering provides high performance but is not viable when power and computational resources must be optimized. This study investigates the application of feed-forward comb (FFC) filters to remove both powerline interferences and motion artifacts from raw EMG. FFC filter and EMG envelope extractor can be implemented without computing any multiplication. This approach is particularly suitable for very low-cost, low-power platforms. The performance of the FFC filter was first demonstrated offline by corrupting clean EMG signals with powerline noise and motion artifacts. The correlation coefficients of the filtered signals envelopes and the true envelopes were greater than 0.98 and 0.94 for EMG corrupted by powerline noise and motion artifacts, respectively. Further tests on real, highly noisy EMG signals confirmed these achievements. Finally, the real-time operation of the proposed approach was successfully tested by implementation on a simple Arduino Uno board.
Polarity signaling balances epithelial contractility and mechanical resistance
Authors: Rübsam Matthias , Püllen Robin , Tellkamp Frederik , Bianco Alessandra , Peskoller Marc , Bloch Wilhelm , Green Kathleen J. , Merkel Rudolf , Hoffmann Bernd , Wickström Sara A. , Niessen Carien M.
Published: May 2023

Epithelia maintain a functional barrier during tissue turnover while facing varying mechanical stress. This maintenance requires both dynamic cell rearrangements driven by actomyosin-linked intercellular adherens junctions and ability to adapt to and resist extrinsic mechanical forces enabled by keratin filament-linked desmosomes. How these two systems crosstalk to coordinate cellular movement and mechanical resilience is not known. Here we show that in stratifying epithelia the polarity protein aPKCλ controls the reorganization from stress fibers to cortical actomyosin during differentiation and upward movement of cells. Without aPKC, stress fibers are retained resulting in increased contractile prestress. This aberrant stress is counterbalanced by reorganization and bundling of keratins, thereby increasing mechanical resilience. Inhibiting contractility in aPKCλ−/− cells restores normal cortical keratin networks but also normalizes resilience. Consistently, increasing contractile stress is sufficient to induce keratin bundling and enhance resilience, mimicking aPKC loss. In conclusion, our data indicate that keratins sense the contractile stress state of stratified epithelia and balance increased contractility by mounting a protective response to maintain tissue integrity.
Consensus clustering methodology to improve molecular stratification of non-small cell lung cancer
Authors: Manganaro L. , Bianco S. , Bironzo P. , Cipollini F. , Colombi D. , Corà D. , Corti G. , Doronzo G. , Errico L. , Falco P. , Gandolfi L. , Guerrera F. , Monica V. , Novello S. , Papotti M. , Parab S. , Pittaro A. , Primo L. , Righi L. , Sabbatini G. , Sandri A. , Vattakunnel S. , Bussolino F. , Scagliotti G.V.
Published: May 2023

Recent advances in machine learning research, combined with the reduced sequencing costs enabled by modern next-generation sequencing, paved the way to the implementation of precision medicine through routine multi-omics molecular profiling of tumours. Thus, there is an emerging need of reliable models exploiting such data to retrieve clinically useful information. Here, we introduce an original consensus clustering approach, overcoming the intrinsic instability of common clustering methods based on molecular data. This approach is applied to the case of non-small cell lung cancer (NSCLC), integrating data of an ongoing clinical study (PROMOLE) with those made available by The Cancer Genome Atlas, to define a molecular-based stratification of the patients beyond, but still preserving, histological subtyping. The resulting subgroups are biologically characterized by well-defined mutational and gene-expression profiles and are significantly related to disease-free survival (DFS). Interestingly, it was observed that (1) cluster B, characterized by a short DFS, is enriched in KEAP1 and SKP2 mutations, that makes it an ideal candidate for further studies with inhibitors, and (2) over- and under-representation of inflammation and immune systems pathways in squamous-cell carcinomas subgroups could be potentially exploited to stratify patients treated with immunotherapy.
Prediction of mammalian tissue-specific CLOCK–BMAL1 binding to E-box DNA motifs
Authors: Marri Daniel , Filipovic David , Kana Omar , Tischkau Shelley , Bhattacharya Sudin
Published: May 2023

The Brain and Muscle ARNTL-Like 1 protein (BMAL1) forms a heterodimer with either Circadian Locomotor Output Cycles Kaput (CLOCK) or Neuronal PAS domain protein 2 (NPAS2) to act as a master regulator of the mammalian circadian clock gene network. The dimer binds to E-box gene regulatory elements on DNA, activating downstream transcription of clock genes. Identification of transcription factor binding sites and genomic features that correlate to DNA binding by BMAL1 is a challenging problem, given that CLOCK–BMAL1 or NPAS2–BMAL1 bind to several distinct binding motifs (CANNTG) on DNA. Using three different types of tissue-specific machine learning models with features based on (1) DNA sequence, (2) DNA sequence plus DNA shape, and (3) DNA sequence and shape plus histone modifications, we developed an interpretable predictive model of genome-wide BMAL1 binding to E-box motifs and dissected the mechanisms underlying BMAL1–DNA binding. Our results indicated that histone modifications, the local shape of the DNA, and the flanking sequence of the E-box motif are sufficient predictive features for BMAL1–DNA binding. Our models also provide mechanistic insights into tissue specificity of DNA binding by BMAL1.
A novel HIV model through fractional enlarged integral and differential operators
Authors: Barakat M. A. , Hyder Abd-Allah , Almoneef Areej A.
Published: May 2023

This article presents a novel mathematical fractional model to examine the transmission of HIV. The new HIV model is built using recently fractional enlarged differential and integral operators. The existence and uniqueness findings for the suggested fractional HIV model are investigated using Leray–Schauder nonlinear alternative (LSNA) and Banach’s fixed point (BFP) theorems. Furthermore, multiple types of Ulam stability (U-S) are created for the fractional model of HIV. It is straightforward to identify that the gained findings may be decreased to many results obtained in former works of literature.
Design of infrared optical absorber using silver nanorings array made by a top-down process
Authors: Bouanane I. , Bedu F. , Ozerov I. , Sciacca B. , Santinacci L. , Duché D. , Berginc G. , Escoubas L. , Margeat O. , Le Rouzo J.
Published: May 2023

This paper presents the numerical simulation and fabrication of a metasurface composed of silver nanorings with a split-ring gap. These nanostructures can exhibit optically-induced magnetic responses with unique possibilities to control absorption at optical frequencies. The absorption coefficient of the silver nanoring was optimized by performing a parametric study with Finite Difference Time Domain (FDTD) simulations. The absorption and scattering cross sections of the nanostructures are numerically calculated to assess the impact of the inner and outer radii, the thickness and the split-ring gap of one nanoring, as well as the periodicity factor for a group of four nanorings. This showed full control on resonance peaks and absorption enhancement in the near infrared spectral range. The experimental fabrication of this metasurface made of an array of silver nanorings is achieved by e-beam lithography and metallization. Optical characterizations are then carried out and compared to the numerical simulations. In contrast to usual microwave split-ring resonator metasurfaces reported in literature, the present study shows both the realization by a top-down process and modelling performed in the infrared frequency range.
Changes in perceived peripersonal space following the rubber hand illusion
Authors: Smit M. , Dijkerman H. C. , Kurstjens V. , de Haan A. M. , van der Ham I. J. M. , van der Smagt M. J.
Published: May 2023

Peripersonal space (PPS), the region immediately surrounding the body is essential for bodily protection and goal directed action. Previous studies have suggested that the PPS is anchored to one’s own body and in the current study we investigated whether the PPS could be modulated by changes in perceived body ownership. While theoretically important, this anchoring can also have implications for patients with altered body perception. The rubber hand illusion (RHI) is a way to manipulate body ownership. We hypothesized that after induction of a left hand RHI, the perceived space around the body shifts to the right. Sixty-five participants performed a landmark task before and after a left hand RHI. In the landmark task, participants had to determine whether a vertical landmark line was left or right from the center of a horizontal screen. One group of the participants was exposed to synchronous stroking, the other group experienced asynchronous stroking. Results showed a shift in space to the right (e.g. away from the own arm), but only for the ‘synchronous stroking’ group. These results suggest that the relevant action space becomes linked to the fake hand. Critically, subjective ownership experience did not correlate with this shift, but proprioceptive drift did. This suggests that multisensory integration of bodily information drives this shift in space around the body and not feelings of ownership.
A novel of WS2–MoCuO3 supported with graphene quantum dot as counter electrode for dye-sensitized solar cells application
Authors: Areerob Yonrapach , Oh Won-Chun , Hamontree Chaowalit , Nachaithong Theeranuch , Nijpanich Supinya , Pattarith Kongsak
Published: May 2023

A novel tungsten disulfide-molybdenum copper oxide composite supported with graphene quantum dots (WM@GQDs) has been synthesized as a counter electrode (CE) for dye-sensitized solar cells (DSSCs) using a simple and low-cost ultrasonication method. The unique structure of WM@GQDs exhibits excellent power conversion efficiency due to its high catalytic activity and charge transport properties. In addition, the graphene quantum dots (GQDs) provide more active sites in the zero-dimensional materials for an I/I3− redox reaction which can improve the electrical and optical properties of the composite. The results indicate that the amount of GQDs in the composite affect the effectiveness of solar devices. When 0.9%wt of GQDs was used, the WM@GQDs composite achieved an efficiency of 10.38%, which is higher than that of the expensive platinum CE under the same conditions. The mechanism behind the improved power conversion efficiency (PCE) of the composite sample is also discussed in detail. Therefore, WM@GQDs can be an efficient material to replace platinum in DSSCs as a CE.
Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19
Authors: Malesevic Stefan , Sievi Noriane A. , Baumgartner Patrick , Roser Katharina , Sommer Grit , Schmidt Dörthe , Vallelian Florence , Jelcic Ilijas , Clarenbach Christian F. , Kohler Malcolm
Published: May 2023

A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL. In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George’s Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms. Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic. Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.

Trial registration: The study is registered on www.ClinicalTrials.gov, NCT04793269.
Millisecond flash lamp curing for porosity generation in thin films
Authors: Attallah Ahmed G. , Prucnal Slawomir , Buttering Maik , Hirschmann Eric , Koehler Nicole , Schulz Stefan E. , Wagner Andreas , Liedke Maciej O.
Published: May 2023

Flash lamp annealing (FLA) with millisecond pulse durations is reported as a novel curing method for pore precursor's degradation in thin films. A case study on the curing of dielectric thin films is presented. FLA-cured films are being investigated by means of positron annihilation spectroscopy (PAS) and Fourier-transform infrared (FTIR) spectroscopy in order to quantify the nm-scale porosity and post-treatment chemistry, respectively. Results from positron annihilation reveal the onset of the formation of porous voids inside the samples at 6 ms flash treatment time. Moreover, parameter's adjustment (flash duration and energy density) allows for identifying the optimum conditions of effective curing. Within such a systematic investigation, positron results indicate that FLA is able to decompose the porogen (pore precursors) and to generate interconnected (open porosity) or isolated pore networks with self-sealed pores in a controllable way. Furthermore, FTIR results demonstrate the structural evolution after FLA, that help for setting the optimal annealing conditions whereby only a residual amount of porogen remains and at the same time a well-densified matrix, and a hydrophobic porous structures are created. Raman spectroscopy suggests that the curing-induced self-sealing layer developed at the film surface is a graphene oxide-like layer, which could serve as the outside sealing of the pore network from intrusions.
Radiomics models based on multisequence MRI for predicting PD-1/PD-L1 expression in hepatocellular carcinoma
Authors: Gong Xue-Qin , Liu Ning , Tao Yun-Yun , Li Li , Li Zu-Mao , Yang Lin , Zhang Xiao-Ming
Published: May 2023

The purpose of this study was to explore the effectiveness of radiomics based on multisequence MRI in predicting the expression of PD-1/PD-L1 in hepatocellular carcinoma (HCC). One hundred and eight patients with HCC who underwent contrast-enhanced MRI 2 weeks before surgical resection were enrolled in this retrospective study. Corresponding paraffin sections were collected for immunohistochemistry to detect the expression of PD-1 and PD-L1. All patients were randomly divided into a training cohort and a validation cohort at a ratio of 7:3. Univariate and multivariate analyses were used to select potential clinical characteristics related to PD-1 and PD-L1 expression. Radiomics features were extracted from the axial fat-suppression T2-weighted imaging (FS-T2WI) images and the arterial phase and portal venous phase images from the axial dynamic contrast-enhanced MRI, and the corresponding feature sets were generated. The least absolute shrinkage and selection operator (LASSO) was used to select the optimal radiomics features for analysis. Logistic regression analysis was performed to construct single-sequence and multisequence radiomics and radiomic-clinical models. The predictive performance was judged by the area under the receiver operating characteristic curve (AUC) in the training and validation cohorts. In the whole cohort, PD-1 expression was positive in 43 patients, and PD-L1 expression was positive in 34 patients. The presence of satellite nodules served as an independent predictor of PD-L1 expression. The AUC values of the FS-T2WI, arterial phase, portal venous phase and multisequence models in predicting the expression of PD-1 were 0.696, 0.843, 0.863, and 0.946 in the training group and 0.669, 0.792, 0.800 and 0.815 in the validation group, respectively. The AUC values of the FS-T2WI, arterial phase, portal venous phase, multisequence and radiomic-clinical models in predicting PD-L1 expression were 0.731, 0.800, 0.800, 0.831 and 0.898 in the training group and 0.621, 0.743, 0.771, 0.810 and 0.779 in the validation group, respectively. The combined models showed better predictive performance. The results of this study suggest that a radiomics model based on multisequence MRI has the potential to predict the preoperative expression of PD-1 and PD-L1 in HCC, which could become an imaging biomarker for immune checkpoint inhibitor (ICI)-based treatment.
Slow advancement of the endotracheal tube during fiberoptic-guided tracheal intubation reduces the severity of postoperative sore throat
Authors: Kim Hyunjee , Kim Jeong Eon , Kim Yeongun , Hong Seong Wook , Jung Hoon
Published: May 2023

Although fiberoptic-guided tracheal intubation is a gentler method than using a direct laryngoscope, injury may occur owing to impingement between the distal edge of the endotracheal tube and the glottis. This study aimed to investigate the effects of endotracheal tube advancement speed during fiberoptic-guided intubation on airway symptoms postoperatively. We randomized patients scheduled for laparoscopic gynecological surgery to either Group C or S. When advancing the tube over the bronchoscope, the operator advanced the tube at a normal speed in Group C and at a slower speed in Group S. The speed in Group S was approximately half that in Group C. The target outcomes were the severity of postoperative sore throat, hoarseness, and cough. Patients in Group C experienced a more severe sore throat than those in Group S at 3 and 24 h postoperatively (p = 0.001 and p = 0.012, respectively). However, the severity of hoarseness and cough postoperatively were not significantly different between the groups. In conclusion, the slow advancement of the endotracheal tube during fiberoptic-guided intubation can reduce sore throat severity.
Behavioral and oscillatory signatures of switch costs in highly proficient bilinguals
Authors: Timofeeva Polina , Quiñones Ileana , Geng Shuang , de Bruin Angela , Carreiras Manuel , Amoruso Lucia
Published: May 2023

Bilinguals with a high proficiency in their first (L1) and second language (L2) often show comparable reaction times when switching from their L1 to L2 and vice-versa (“symmetrical switch costs”). However, the neurophysiological signatures supporting this effect are not well understood. Here, we ran two separate experiments and assessed behavioral and MEG responses in highly proficient Spanish-Basque bilinguals while they overtly name pictures in a mixed-language context. In the behavioral experiment, bilinguals were slower when naming items in switch relative to non-switch trials, and this switch cost was comparable for both languages (symmetrical). The MEG experiment mimicked the behavioral one, with switch trials showing more desynchronization than non-switch trials across languages (symmetric neural cost) in the alpha band (8–13 Hz). Source-localization revealed the engagement of right parietal and premotor areas, which have been linked to language selection and inhibitory control; and of the left anterior temporal lobe (ATL), a cross-linguistic region housing conceptual knowledge that generalizes across languages. Our results suggest that highly proficient bilinguals implement a language-independent mechanism, supported by alpha oscillations, which is involved in cue-based language selection and facilitates conceptually-driven lexical access in the ATL, possibly by inhibiting non-target lexical items or disinhibiting target ones.
An efficient quantum partial differential equation solver with chebyshev points
Authors: Oz Furkan , San Omer , Kara Kursat
Published: May 2023

Differential equations are the foundation of mathematical models representing the universe’s physics. Hence, it is significant to solve partial and ordinary differential equations, such as Navier–Stokes, heat transfer, convection–diffusion, and wave equations, to model, calculate and simulate the underlying complex physical processes. However, it is challenging to solve coupled nonlinear high dimensional partial differential equations in classical computers because of the vast amount of required resources and time. Quantum computation is one of the most promising methods that enable simulations of more complex problems. One solver developed for quantum computers is the quantum partial differential equation (PDE) solver, which uses the quantum amplitude estimation algorithm (QAEA). This paper proposes an efficient implementation of the QAEA by utilizing Chebyshev points for numerical integration to design robust quantum PDE solvers. A generic ordinary differential equation, a heat equation, and a convection–diffusion equation are solved. The solutions are compared with the available data to demonstrate the effectiveness of the proposed approach. We show that the proposed implementation provides a two-order accuracy increase with a significant reduction in solution time.
Examining the relationship between risky sexual behavior and suicidal thoughts among unmarried adolescents in India
Authors: Maurya Chanda , Muhammad T. , Thakkar Shriya
Published: May 2023

Addressing the problem of suicidal thoughts in adolescents requires understanding the associated risk factors. Multiple studies have shown that risky sexual behavior affected the adolescents’ psychological health that leads to their suicidal thoughts, behaviors and attempts. This study aimed to identify the association between various risky sexual behaviours and suicidal thoughts among unmarried adolescents in India. We used data collected from 4221 unmarried adolescent boys and 5987 unmarried adolescent girls aged 10–19 years, from the two rounds of the Understanding the Lives of Adolescents and Young Adults (UDAYA) survey. Descriptive analysis was done to observe changes in the selected variables from wave-1 to wave-2. Random effect regression analysis was used to estimate the association of suicidal thoughts among unmarried adolescents with their risky sexual behaviours. The percentage of adolescent boys having suicidal thoughts increased from 1.35% in wave 1 to 2.19% in wave 2. Among adolescent girls, the percentage increased from 2.92% in wave 1 to 5.05% in wave 2. A proportion of 3.26% adolescent boys had more than one sexual partner during wave 1 whereas in wave 2, it rose to 8.71%, while in case of adolescent girls, the estimates only increased from 0.26% at wave 1 to 0.78% at wave 2. Nearly 4.55% boys and 1.37% girls had early sexual debut. Almost five percentage boys were sexually active at wave 1 whereas in wave 2, it rose to 13.56%, while among adolescent girls, the estimates decreased from 1.54% at wave 1 to 1.51% at wave 2. Contraceptive use increased over time among both adolescent boy and girls. Also, a large proportion of adolescent boys reported watching pornography (27.08% at waive 1 and 49.39% at wave 2) compared to adolescent girls (4.46% at wave 1 and 13.10% at wave 2). Adolescents who had more than one sexual partner [Coef: 0.04; p < 0.001], exposed to early sexual debut [Coef; 0.019; p < 0.01], sexually active [Coef: 0.058; p < 0.001] and reported watching pornography [Coef: 0.017; p < 0.001] were more likely to have suicidal thoughts. Adolescent boys and girls with risky sexual behaviors are likely to be at a higher risk of suicidal ideation, and thus, they should be treated with special care and attention by local healthcare practitioners.
Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance
Authors: Verheijden Rik J. , van Eijs Mick J. M. , May Anne M. , van Wijk Femke , Suijkerbuijk Karijn P. M.
Published: May 2023

Immune checkpoint inhibitors (ICIs) have changed perspectives for patients with cancer, but come with severe immune-related adverse events (irAEs). To prevent fatality or chronicity, these irAEs are often promptly treated with high-dose immunosuppressants. Until recently, evidence on the effects of irAE management on ICI efficacy has been sparse. As a result, algorithms for irAE management are mostly expert-opinion based and barely consider possible detrimental effects of immunosuppressants on ICI efficacy. However, recent growing evidence suggests that vigorous immunosuppressive management of irAEs comes with unfavourable effects on ICI efficacy and survival. With expansion of the indications of ICIs, evidence-based treatment of irAEs without hampering tumour control becomes more and more important. In this review, we discuss novel evidence from pre-clinical and clinical studies on the effects of different irAE management regimens including corticosteroids, TNF inhibition and tocilizumab on cancer control and survival. We provide recommendations for pre-clinical research, cohort studies and clinical trials that can help clinicians in tailored irAE management, minimising patients’ burden while maintaining ICI efficacy.
Non-thermal Tomonaga-Luttinger liquid eventually emerging from hot electrons in the quantum Hall regime
Authors: Suzuki Kotaro , Hata Tokuro , Sato Yuya , Akiho Takafumi , Muraki Koji , Fujisawa Toshimasa
Published: May 2023

Dynamics of integrable systems, such as Tomonaga-Luttinger (TL) liquids, is deterministic, and the absence of stochastic thermalization processes provides unique characteristics, such as long-lived non-thermal metastable states with many conserved quantities. Here, we show such non-thermal states can emerge even when the TL liquid is excited with extremely high-energy hot electrons in chiral quantum-Hall edge channels. This demonstrates the robustness of the integrable model against the excitation energy. Crossover from the single-particle hot electrons to the many-body TL liquid is investigated by using on-chip detectors with a quantum point contact and a quantum dot. The charge dynamics can be understood with a single-particle picture only for hot electrons. The resulting electron-hole plasma in the TL liquid shows a non-thermal metastable state, in which warm and cold electrons coexist without further thermalization. The multi-temperature constituents are attractive for transporting information with conserved quantities along the channels.