bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of clozapine in psychotic disorders—a systematic quantitative meta-review
Authors: Wagner Elias , Siafis Spyridon , Fernando Piyumi , Falkai Peter , Honer William G. , Röh Astrid , Siskind Dan , Leucht Stefan , Hasan Alkomiet
Published: September 2021

A recent increase in the literature regarding the evidence base for clozapine has made it increasingly difficult for clinicians to judge “best evidence” for clozapine use. As such, we aimed at elucidating the state-of-the-art for clozapine with regard to efficacy, effectiveness, tolerability, and management of clozapine and clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2. Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation antipsychotics (FGAs) and to pooled FGAs/second-generation antipsychotics (SGAs) in treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of clozapine compared to FGAs and most other SGAs in schizophrenia and suggests beneficial efficacy outcomes in bipolar disorder and Parkinson’s disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of clozapine in schizophrenia-spectrum disorders and future studies should be directed into multidimensional clozapine side-effect management to foster evidence and to inform future guidelines.
KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1
Authors: Hua Qing , Sun Zhirong , Liu Yi , Shen Xuefang , Zhao Weiwei , Zhu Xiaoyan , Xu Pingbo
Published: September 2021

Kallikrein-related peptidase 8 (KLK8) acts as an oncogene or anti-oncogene in various tumours, and the abnormal expression of KLK8 is involved in the carcinogenesis of several tumours. However, the role of KLK8 in colorectal cancer (CRC) and the underlying mechanism remain largely unclear. In this study, the carcinogenic effect of KLK8 was determined via CCK-8 and colony formation assays in vitro and a xenograft model in nude mice in vivo. The metastasis-promoting effect of KLK8 was investigated with transwell migration and invasion assays and wound-healing assay in vitro and a metastasis model in nude mice in vivo. Bioinformatics analyses and mechanistic experiments were conducted to elucidate the molecular mechanism. Herein, we reported that KLK8 had a promotive effect on the proliferation, migration and invasion of RKO and SW480 cells. Epithelial−mesenchymal transition (EMT) played an important role in the promotive effects of KLK8 on CRC. In addition, protease-activated receptor-1 (PAR-1) antagonist SCH79797 but not protease-activated receptor-2 (PAR-2) antagonist FSLLRY-NH2 attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells. PAR-1 antagonist SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, SCH79797 could reverse the positive impact of KLK8 on the EMT process in CRC both in vitro and in vivo. Taken together, these findings demonstrated for the first time that KLK8 promoted EMT and CRC progression, and this effect might be, at least partly mediated by PAR1-dependent pathway.
Terahertz response of monolayer and few-layer WTe2 at the nanoscale
Authors: Jing Ran , Shao Yinming , Fei Zaiyao , Lo Chiu Fan Bowen , Vitalone Rocco A. , Ruta Francesco L. , Staunton John , Zheng William J.-C , Mcleod Alexander S. , Sun Zhiyuan , Jiang Bor-yuan , Chen Xinzhong , Fogler Michael M. , Millis Andrew J. , Liu Mengkun , Cobden David H. , Xu Xiaodong , Basov D. N.
Published: September 2021

Tungsten ditelluride (WTe2) is an atomically layered transition metal dichalcogenide whose physical properties change systematically from monolayer to bilayer and few-layer versions. In this report, we use apertureless scattering-type near-field optical microscopy operating at Terahertz (THz) frequencies and cryogenic temperatures to study the distinct THz range electromagnetic responses of mono-, bi- and trilayer WTe2 in the same multi-terraced micro-crystal. THz nano-images of monolayer terraces uncovered weakly insulating behavior that is consistent with transport measurements. The near-field signal on bilayer regions shows moderate metallicity with negligible temperature dependence. Subdiffractional THz imaging data together with theoretical calculations involving thermally activated carriers favor the semimetal scenario with $$\Delta \approx -10\,{{{\rm{meV}}}}$$
Δ
≈
−
10

meV
over the semiconductor scenario for bilayer WTe2. Also, we observed clear metallic behavior of the near-field signal on trilayer regions. Our data are consistent with the existence of surface plasmon polaritons in the THz range confined to trilayer terraces in our specimens. Finally, data for microcrystals up to 12 layers thick reveal how the response of a few-layer WTe2 asymptotically approaches the bulk limit.
Mechanistic insight into the active centers of single/dual-atom Ni/Fe-based oxygen electrocatalysts
Authors: Wan Wenchao , Zhao Yonggui , Wei Shiqian , Triana Carlos A. , Li Jingguo , Arcifa Andrea , Allen Christopher S. , Cao Rui , Patzke Greta R.
Published: September 2021

Single-atom catalysts with maximum metal utilization efficiency show great potential for sustainable catalytic applications and fundamental mechanistic studies. We here provide a convenient molecular tailoring strategy based on graphitic carbon nitride as support for the rational design of single-site and dual-site single-atom catalysts. Catalysts with single Fe sites exhibit impressive oxygen reduction reaction activity with a half-wave potential of 0.89 V vs. RHE. We find that the single Ni sites are favorable to promote the key structural reconstruction into bridging Ni-O-Fe bonds in dual-site NiFe SAC. Meanwhile, the newly formed Ni-O-Fe bonds create spin channels for electron transfer, resulting in a significant improvement of the oxygen evolution reaction activity with an overpotential of 270 mV at 10 mA cm−2. We further reveal that the water oxidation reaction follows a dual-site pathway through the deprotonation of *OH at both Ni and Fe sites, leading to the formation of bridging O2 atop the Ni-O-Fe sites.
Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases
Authors: Fernandez Lahore Gonzalo , Förster Michael , Johannesson Martina , Sabatier Pierre , Lönnblom Erik , Aoun Mike , He Yibo , Nandakumar Kutty Selva , Zubarev Roman A. , Holmdahl Rikard
Published: September 2021

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulatesCd2expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find thatCD2polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.
X-ray study of ferroic octupole order producing anomalous Hall effect
Authors: Kimata Motoi , Sasabe Norimasa , Kurita Kensuke , Yamasaki Yuichi , Tabata Chihiro , Yokoyama Yuichi , Kotani Yoshinori , Ikhlas Muhammad , Tomita Takahiro , Amemiya Kenta , Nojiri Hiroyuki , Nakatsuji Satoru , Koretsune Takashi , Nakao Hironori , Arima Taka-hisa , Nakamura Tetsuya
Published: September 2021

Recently found anomalous Hall, Nernst, magnetooptical Kerr, and spin Hall effects in the antiferromagnets Mn3X (X = Sn, Ge) are attracting much attention for spintronics and energy harvesting. Since these materials are antiferromagnets, the origin of these functionalities is expected to be different from that of conventional ferromagnets. Here, we report the observation of ferroic order of magnetic octupole in Mn3Sn by X-ray magnetic circular dichroism, which is only predicted theoretically so far. The observed signals are clearly decoupled with the behaviors of uniform magnetization, indicating that the present X-ray magnetic circular dichroism is not arising from the conventional magnetization. We have found that the appearance of this anomalous signal coincides with the time reversal symmetry broken cluster magnetic octupole order. Our study demonstrates that the exotic material functionalities are closely related to the multipole order, which can produce unconventional cross correlation functionalities.
A scalable workflow to characterize the human exposome
Authors: Hu Xin , Walker Douglas I. , Liang Yongliang , Smith Matthew Ryan , Orr Michael L. , Juran Brian D. , Ma Chunyu , Uppal Karan , Koval Michael , Martin Greg S. , Neujahr David C. , Marsit Carmen J. , Go Young-Mi , Pennell Kurt D. , Miller Gary W. , Lazaridis Konstantinos N. , Jones Dean P.
Published: September 2021

Complementing the genome with an understanding of the human exposome is an important challenge for contemporary science and technology. Tens of thousands of chemicals are used in commerce, yet cost for targeted environmental chemical analysis limits surveillance to a few hundred known hazards. To overcome limitations which prevent scaling to thousands of chemicals, we develop a single-step express liquid extraction and gas chromatography high-resolution mass spectrometry analysis to operationalize the human exposome. We show that the workflow supports quantification of environmental chemicals in human plasma (200 µL) and tissue (≤100 mg) samples. The method also provides high resolution, sensitivity and selectivity for exposome epidemiology of mass spectral features without a priori knowledge of chemical identity. The simplicity of the method can facilitate harmonization of environmental biomonitoring between laboratories and enable population level human exposome research with limited sample volume.
Quantum fluids of light in all-optical scatterer lattices
Authors: Alyatkin S. , Sigurdsson H. , Askitopoulos A. , Töpfer J. D. , Lagoudakis P. G.
Published: September 2021

One of the recently established paradigms in condensed matter physics is examining a system’s behaviour in artificial potentials, giving insight into phenomena of quantum fluids in hard-to-reach settings. A prominent example is the matter-wave scatterer lattice, where high energy matter waves undergo transmission and reflection through narrow width barriers leading to stringent phase matching conditions with lattice band formation. In contrast to evanescently coupled lattice sites, the realisation of a scatterer lattice for macroscopic matter-wave fluids has remained elusive. Here, we implement a system of exciton-polariton condensates in a non-Hermitian Lieb lattice of scatterer potentials. By fine tuning the lattice parameters, we reveal a nonequilibrium phase transition between distinct regimes of polariton condensation: a scatterer lattice of gain guided polaritons condensing on the lattice potential maxima, and trapped polaritons condensing in the potential minima. Our results pave the way towards unexplored physics of non-Hermitian fluids in non-stationary mixtures of confined and freely expanding waves.
Structure of a Ty1 restriction factor reveals the molecular basis of transposition copy number control
Authors: Cottee Matthew A. , Beckwith Sean L. , Letham Suzanne C. , Kim Sarah J. , Young George R. , Stoye Jonathan P. , Garfinkel David J. , Taylor Ian A.
Published: September 2021

Excessive replication of Saccharomyces cerevisiae Ty1 retrotransposons is regulated by Copy Number Control, a process requiring the p22/p18 protein produced from a sub-genomic transcript initiated within Ty1 GAG. In retrotransposition, Gag performs the capsid functions required for replication and re-integration. To minimize genomic damage, p22/p18 interrupts virus-like particle function by interaction with Gag. Here, we present structural, biophysical and genetic analyses of p18m, a minimal fragment of Gag that restricts transposition. The 2.8 Å crystal structure of p18m reveals an all α-helical protein related to mammalian and insect ARC proteins. p18m retains the capacity to dimerise in solution and the crystal structures reveal two exclusive dimer interfaces. We probe our findings through biophysical analysis of interface mutants as well as Ty1 transposition and p18m restriction in vivo. Our data provide insight into Ty1 Gag structure and suggest how p22/p18 might function in restriction through a blocking-of-assembly mechanism.
Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
Authors: Heestermans Marco , Naudin Clément , Mailer Reiner K. , Konrath Sandra , Klaetschke Kristin , Jämsä Anne , Frye Maike , Deppermann Carsten , Pula Giordano , Kuta Piotr , Friese Manuel A. , Gelderblom Mathias , Sickmann Albert , Preston Roger J. S. , Nofer Jerzy-Roch , Rose-John Stefan , Butler Lynn M. , Salomon Ophira , Stavrou Evi X. , Renné Thomas
Published: September 2021

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer
Authors: Konstantinopoulos Panagiotis A. , da Costa Alexandre André B. A. , Gulhan Doga , Lee Elizabeth K. , Cheng Su-Chun , Hendrickson Andrea E. Wahner , Kochupurakkal Bose , Kolin David L. , Kohn Elise C. , Liu Joyce F. , Stover Elizabeth H. , Curtis Jennifer , Tayob Nabihah , Polak Madeline , Chowdhury Dipanjan , Matulonis Ursula A. , Färkkilä Anniina , D’Andrea Alan D. , Shapiro Geoffrey I.
Published: September 2021

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.
Development of a model-inference system for estimating epidemiological characteristics of SARS-CoV-2 variants of concern
Authors: Yang Wan , Shaman Jeffrey
Published: September 2021

To support COVID-19 pandemic planning, we develop a model-inference system to estimate epidemiological properties of new SARS-CoV-2 variants of concern using case and mortality data while accounting for under-ascertainment, disease seasonality, non-pharmaceutical interventions, and mass-vaccination. Applying this system to study three variants of concern, we estimate that B.1.1.7 has a 46.6% (95% CI: 32.3–54.6%) transmissibility increase but nominal immune escape from protection induced by prior wild-type infection; B.1.351 has a 32.4% (95% CI: 14.6–48.0%) transmissibility increase and 61.3% (95% CI: 42.6–85.8%) immune escape; and P.1 has a 43.3% (95% CI: 30.3–65.3%) transmissibility increase and 52.5% (95% CI: 0–75.8%) immune escape. Model simulations indicate that B.1.351 and P.1 could outcompete B.1.1.7 and lead to increased infections. Our findings highlight the importance of preventing the spread of variants of concern, via continued preventive measures, prompt mass-vaccination, continued vaccine efficacy monitoring, and possible updating of vaccine formulations to ensure high efficacy.
Examining the effects of cigarette smoke on mouse lens through a multi OMIC approach
Authors: Khan Shahid Y. , Ali Muhammad , Jang Yura , Ryu Taekyung , Schwab Andrew J. , Ingram Brian O. , Cable Peter H. , Na Chan Hyun , Handa James T. , Riazuddin S. Amer
Published: September 2021

Here, we report a multi OMIC (transcriptome, proteome, and metabolome) approach to investigate molecular changes in lens fiber cells (FC) of mice exposed to cigarette smoke (CS). Pregnant mice were placed in a whole-body smoke chamber and a few days later pups were born, which were exposed to CS for 5 hours/day, 5 days/week for a total of 3½ months. We examined the mice exposed to CS for CS-related cataractogenesis after completion of the CS exposure but no cataracts were observed. Lenses of CS-exposed and age-matched, untreated control mice were extracted and lens FC were subjected to multi OMIC profiling. We identified 348 genes, 130 proteins, and 14 metabolites exhibiting significant (p < 0.05) differential levels in lens FC of mice exposed to CS, corresponding to 3.6%, 4.3%, and 5.0% of the total genes, protein, and metabolites, respectively identified in this study. Our multi OMIC approach confirmed that only a small fraction of the transcriptome, the proteome, and the metabolome was perturbed in the lens FC of mice exposed to CS, which suggests that exposure of CS had a minimal effect on the mouse lens. It is worth noting that while our results confirm that CS exposure does not have a substantial impact on the molecular landscape of the mouse lens FC, we cannot rule out that CS exposure for longer durations and/or in combination with other morbidities or environmental factors would have a more robust effect and/or result in cataractogenesis.
Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2
Authors: López-Cortés Georgina I. , Palacios-Pérez Miryam , Zamudio Gabriel S. , Veledíaz Hannya F. , Ortega Enrique , José Marco V.
Published: September 2021

As the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 spike protein from homologue proteins of Betacoronavirus, as well as to the spikes from human clinical isolates of the virus. Specifically, Tyr and Asn have higher occurrence rates on the Receptor Binding Domain (RBD) and in the overall sequence of spike proteins of Betacoronavirus, whereas His and Arg have lower occurrence rates. The in vivo evolutionary phenomenon of SARS-CoV-2 shows that Glu, Lys, Phe, and Val have the highest probability of occurrence in the emergent viral particles. Amino acids that have higher occurrence than the expected by the neutral control, are favorable and are fixed in the sequence while the ones that have lower occurrence than expected, influence the stability and/or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or its variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. We explored the consequences of those selected mutations in the structure and protein – protein interaction with the receptor. Altogether all these forces have shaped the spike protein and the continually evolving variants.
Ene-reductase transformation of massoia lactone to δ-decalactone in a continuous-flow reactor
Authors: Szczepańska Ewa , Colombo Danilo , Tentori Francesca , Olejniczak Teresa , Brenna Elisabetta , Monti Daniela , Boratyński Filip
Published: September 2021

The demand for natural food flavorings increases every year. Biotransformation has become an attractive approach to obtain natural products. In this work, enantiomerically pure (R)-(+)-δ-decalactone was obtained by reduction of the C=C double bond of natural massoia lactone in a continuous-flow reactor. Of 13 different ene-reductases isolated, purified and tested, OYE3 was found to be the most efficient biocatalyst. The selected biocatalyst, either in the form of purified enzyme, cell lysate, whole cells or immobilized cells, was tested in the batch system as well as in the packed-bed flow bioreactor. The biotransformation performed in batch mode, using Ca2+-alginate immobilized cells of Escherichia coli BL21(DE3)/pET30a-OYE3, furnished the desired product with complete conversion in 30 min. The process was intensified using a continuous-flow reactor-membrane filtration system (flow 0.1 mL/min, substrate concentration 10 mM, pH 7, 24 °C) with cell lysate as biocatalyst combined with a cofactor regeneration system, which allowed obtaining > 99% bioconversion of massoia lactone.
Destruction mechanisms of ozone over SARS-CoV-2
Authors: Ataei-Pirkooh Angila , Alavi Ali , Kianirad Mehran , Bagherzadeh Kowsar , Ghasempour Alireza , Pourdakan Omid , Adl Reza , Kiani Seyed Jalal , Mirzaei Mehdi , Mehravi Bita
Published: September 2021

In this pandemic SARS-CoV-2 crisis, any attempt to contain and eliminate the virus will also stop its spread and consequently decrease the risk of severe illness and death. While ozone treatment has been suggested as an effective disinfection process, no precise mechanism of action has been previously reported. This study aimed to further investigate the effect of ozone treatment on SARS-CoV-2. Therefore, virus collected from nasopharyngeal and oropharyngeal swab and sputum samples from symptomatic patients was exposed to ozone for different exposure times. The virus morphology and structure were monitored and analyzed through Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), Atomic Absorption Spectroscopy (AAS), and ATR-FTIR. The obtained results showed that ozone treatment not only unsettles the virus morphology but also alters the virus proteins’ structure and conformation through amino acid disturbance and Zn ion release from the virus non-structural proteins. These results could provide a clearer pathway for virus elimination and therapeutics preparation.
Proliferative diabetic retinopathy transcriptomes reveal angiogenesis, anti-angiogenic therapy escape mechanisms, fibrosis and lymphatic involvement
Authors: Korhonen Ani , Gucciardo Erika , Lehti Kaisa , Loukovaara Sirpa
Published: September 2021

Proliferative diabetic retinopathy (PDR) is a sight-threatening diabetic complication in urgent need of new therapies. In this study we identify potential molecular mechanisms and target candidates in the pathogenesis of PDR fibrovascular tissue formation. We performed mRNA sequencing of RNA isolated from eleven excised fibrovascular membranes of type 1 diabetic PDR patients and two non-diabetic patients with rhegmatogenous retinal detachment with proliferative vitreoretinopathy. We determined differentially expressed genes between these groups and performed pathway and gene ontology term enrichment analyses to identify potential underlying mechanisms, pathways, and regulators. Multiple pro-angiogenic processes, including VEGFA-dependent and -independent pathways, as well as processes related to lymphatic development, epithelial to mesenchymal transition (EMT), wound healing, inflammation, fibrosis, and extracellular matrix (ECM) composition, were overrepresented in PDR. Overrepresentation of different angiogenic processes may help to explain the transient nature of the benefits that many patients receive from current intravitreal anti-angiogenic therapies, highlighting the importance of combinatorial treatments. Enrichment of genes and pathways related to lymphatic development indicates that targeting lymphatic involvement in PDR progression could have therapeutic relevance. Together with overrepresentation of EMT and fibrosis as well as differential ECM composition, these findings demonstrate the complexity of PDR fibrovascular tissue formation and provide avenues for the development of novel treatments.
A genetic risk score using human chromosomal-scale length variation can predict schizophrenia
Authors: Toh Christopher , Brody James P.
Published: September 2021

Studies indicate that schizophrenia has a genetic component, however it cannot be isolated to a single gene. We aimed to determine how well one could predict that a person will develop schizophrenia based on their germ line genetics. We compared 1129 people from the UK Biobank dataset who had a diagnosis of schizophrenia to an equal number of age matched people drawn from the general UK Biobank population. For each person, we constructed a profile consisting of numbers. Each number characterized the length of segments of chromosomes. We tested several machine learning algorithms to determine which was most effective in predicting schizophrenia and if any improvement in prediction occurs by breaking the chromosomes into smaller chunks. We found that the stacked ensemble, performed best with an area under the receiver operating characteristic curve (AUC) of 0.545 (95% CI 0.539–0.550). We noted an increase in the AUC by breaking the chromosomes into smaller chunks for analysis. Using SHAP values, we identified the X chromosome as the most important contributor to the predictive model. We conclude that germ line chromosomal scale length variation data could provide an effective genetic risk score for schizophrenia which performs better than chance.
The importance of environmental microbes for Drosophila melanogaster during seasonal macronutrient variability
Authors: Davies Lucy Rebecca , Loeschcke Volker , Schou Mads F. , Schramm Andreas , Kristensen Torsten N.
Published: September 2021

Experiments manipulating the nutritional environment and the associated microbiome of animals have demonstrated their importance for key fitness components. However, there is little information on how macronutrient composition and bacterial communities in natural food sources vary across seasons in nature and on how these factors affect the fitness components of insects. In this study, diet samples from an orchard compost heap, which is a natural habitat for many Drosophila species and other arthropods, were collected over 9 months covering all seasons in a temperate climate. We developed D. melanogaster on diet samples and investigated stress resistance and life-history traits as well as the microbial community of flies and compost. Nutrient and microbial community analysis of the diet samples showed marked differences in macronutrient composition and microbial community across seasons. However, except for the duration of development on these diet samples and Critical Thermal maximum, fly stress resistance and life-history traits were unaffected. The resulting differences in the fly microbial community were also more stable and less diverse than the microbial community of the diet samples. Our study suggests that when D. melanogaster are exposed to a vastly varying nutritional environment with a rich, diverse microbial community, the detrimental consequences of an unfavourable macronutrient composition are offset by the complex interactions between microbes and nutrients.
Interhemispheric asymmetry during NREM sleep in the dog
Authors: Reicher Vivien , Kis Anna , Simor Péter , Bódizs Róbert , Gácsi Márta
Published: September 2021

Functional hemispheric asymmetry was evidenced in many species during sleep. Dogs seem to show hemispheric asymmetry during wakefulness; however, their asymmetric neural activity during sleep was not yet explored. The present study investigated interhemispheric asymmetry in family dogs using non-invasive polysomnography. EEG recordings during 3-h-long afternoon naps were carried out (N = 19) on two occasions at the same location. Hemispheric asymmetry was assessed during NREM sleep, using bilateral EEG channels. To include periods with high homeostatic sleep pressure and to reduce the variance of the time spent in NREM sleep between dogs, the first two sleep cycles were analysed. Left hemispheric predominance of slow frequency range was detected in the first sleep cycle of sleep recording 1, compared to the baseline level of zero asymmetry as well as to the first sleep cycle of sleep recording 2. Regarding the strength of hemispheric asymmetry, we found greater absolute hemispheric asymmetry in the second sleep cycle of sleep recording 1 and 2 in the frequency ranges of alpha, sigma and beta, compared to the first sleep cycle. Differences between sleep recordings and consecutive sleep cycles might be indicative of adaptation-like processes, but do not closely resemble the results described in humans.
Identification of transcriptome alterations in the prefrontal cortex, hippocampus, amygdala and hippocampus of suicide victims
Authors: Glavan Daniela , Gheorman Victor , Gresita Andrei , Hermann Dirk M. , Udristoiu Ion , Popa-Wagner Aurel
Published: September 2021

Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.
Properties of the lunar gravity assisted transfers from LEO to the retrograde-GEO
Authors: He Bo-yong , Ma Peng-bin , Li Heng-nian
Published: September 2021

The retrograde geostationary earth orbit (retro-GEO) is an Earth’s orbit. It has almost the same orbital altitude with that of a GEO, but an inclination of 180°. A retro-GEO monitor-satellite gives the GEO-assets vicinity space-debris warnings per 12 h. For various reasons, the westward launch direction is not compatible or economical. Thereby the transfer from a low earth orbit (LEO) to the retro-GEO via once lunar swing-by is a priority. The monitor-satellite departures from LEO and inserts into the retro-GEO both using only one tangential maneuver, in this paper, its transfer’s property is investigated. The existence of this transfer is verified firstly in the planar circular restricted three-body problem (CR3BP) model based on the Poincaré-section methodology. Then, the two-impulse values and the perilune altitudes are computed with different transfer durations in the planar CR3BP. Their dispersions are compared with different Sun azimuths in the planar bi-circular restricted four-body problem (BR4BP) model. Besides, the transfer’s inclination changeable capacity via lunar swing-by and the Sun-perturbed inclination changeable capacity are investigated. The results show that the two-impulse fuel-optimal transfer has the duration of 1.76 TU (i.e., 7.65 days) with the minimum values of 4.251 km s−1 in planar CR3BP, this value has a range of 4.249–4.252 km s−1 due to different Sun azimuths in planar BR4BP. Its perilune altitude changes from 552.6 to 621.9 km. In the spatial CR3BP, if the transfer duration is more than or equal to 4.00 TU (i.e., 17.59 days), the lunar gravity assisted transfer could insert the retro-GEO with any inclination. In the spatial BR4BP, the Sun’s perturbation does not affect this conclusion in most cases.
Dangerous demographics in post-bleach corals reveal boom-bust versus protracted declines
Authors: Morais Juliano , Morais Renato A. , Tebbett Sterling B. , Pratchett Morgan S. , Bellwood David R.
Published: September 2021

Thermal-stress events have changed the structure, biodiversity, and functioning of coral reefs. But how these disturbances affect the dynamics of individual coral colonies remains unclear. By tracking the fate of 1069 individual Acropora and massive Porites coral colonies for up to 5 years, spanning three bleaching events, we reveal striking genus-level differences in their demographic response to bleaching (mortality, growth, and recruitment). Although Acropora colonies were locally extirpated, substantial local recruitment and fast growth revealed a marked capacity for apparent recovery. By contrast, almost all massive Porites colonies survived and the majority grew in area; yet no new colonies were detected over the 5 years. Our results highlight contrasting dynamics of boom-and-bust vs. protracted declines in two major coral groups. These dangerous demographics emphasise the need for caution when documenting the susceptibility and perceived resistance or recovery of corals to disturbances.
Thermo-mechanical characterization of shale using nanoindentation
Authors: Wang Yanbo , Porter Debora Lyn , Naleway Steven E. , Newell Pania
Published: September 2021

Shale can be a potential buffer for high-level radioactive nuclear wastes. To be an effective buffer while subject to waste heat, shale's mechanical response at elevated temperature must be known. Many researchers have experimentally characterized the mechanical behavior of various shales at different length scales in adiabatic conditions. However, its mechanical performance at elevated temperatures at the nano-scale remains unknown. To investigate the temperature dependency of nanomechanical properties of shale, we conducted both experimental and numerical studies. In this study, we measured mechanical and fracture properties of shale, such as hardness, elastic modulus, anisotropy, and fracture toughness from 25 °C up to 300 °C at different bedding planes. Statistical analysis of the results suggests that hardness and fracture toughness significantly increased at temperatures from 100 to 300 °C; while, temperature does not have a significant impact on elastic modulus. Data also shows that the bedding plane orientations have a substantial impact on both mechanical and fracture properties of shale at the nano-scale leading to distinct anisotropic behavior at elevated temperature below 100 °C. Additionally, we numerically investigated the mechanical performance of the shale samples at room temperature to gain an insight into its mechanical response through the thickness. Numerical results were validated against the experimental results, confirming the simulation can be used to predict shale deformation at the nano-scale or potentially be used in multi-scale simulations.
Alternate layer by layered self assembly of conjugated and unconjugated Salen based nanowires as capacitive pseudo supercapacitor
Authors: Doroodmand Mohammad Mahdi , Owji Sina
Published: September 2021

A novel electrosynthetic method has been introduced based on alternate layer-by-layered self-assembly of conjugated/unconjugated Salen-based nanowires as a capacitive pseudo-supercapacitor. For this purpose, a three-electrode system consisted of a glassy carbon (GC), Ag/AgCl (Sat’d Cl−) and a Pt rod as working, reference, and counter electrodes, respectively. The electrolyte included the same molar concentration (0.040 mol L−1) of each Salen monomer (as initial precursor), and KCl solution (as supporting electrolyte), besides using KOH solution (0.01 mol L−1, as basic-controlling reagent) inside acetone/water (4:1, V/V) as a solvent. The formation of this self-assembly nanowire was attributed to the control of the electrical conductivity of this polymer during formation of an organometallic complex with K+as responsible complex forming agent. This novel nanowire then played role as a capacitive pseudo-supercapacitor. Based on the chrono—potentiometry, reproducible charge/discharge process for at least 5000 cycles was observed at a potential between − 2.00 and + 1.75 V (vs. Ag/AgCl). The capacity behavior of the polymer was also evidenced using electrochemical impedance spectroscopy. This synthesized polymeric nanowire was adopted as the acceptable pseudo-supercapacitor with real capacity equals to 3110 ± 6 (n = 3) C g−1. This study was considered as the first report at which the self—assembly of organometallic compounds as an efficient pseudo—supercapacitor was introduced.
Humpback whale song recordings suggest common feeding ground occupation by multiple populations
Authors: Schall Elena , Thomisch Karolin , Boebel Olaf , Gerlach Gabriele , Mangia Woods Sari , T. Roca Irene , Van Opzeeland Ilse
Published: September 2021

Humpback whale males are known to sing on their low-latitude breeding grounds, but it is well established that songs are also commonly produced ‘off-season’ on the feeding grounds or during migration. This opens exciting opportunities to investigate migratory aggregations, study humpback whale behavioral plasticity and potentially even assign individual singers to specific breeding grounds. In this study, we analyzed passive acoustic data from 13 recording positions and multiple years (2011–2018) within the Atlantic sector of the Southern Ocean (ASSO). Humpback whale song was detected at nine recording positions in five years. Most songs were recorded in May, austral fall, coinciding with the rapid increase in sea ice concentration at most recording positions. The spatio-temporal pattern in humpback whale singing activity on Southern Ocean feeding grounds is most likely shaped by local prey availability and humpback whale migratory strategies. Furthermore, the comparative analyses of song structures clearly show a differentiation of two song groups, of which one was solely recorded at the western edge of the ASSO and the other song group was recorded throughout the ASSO. This new finding suggests a common feeding ground occupation by multiple humpback whale populations in the ASSO, allowing for cultural and potentially even genetic exchange among populations.
Changes in severity, mortality, and virus genome among a Spanish cohort of patients hospitalized with SARS-CoV-2
Authors: Aznar-Gimeno Rocío , Paño-Pardo J. Ramón , Esteban Luis M. , Labata-Lezaun Gorka , Esquillor-Rodrigo M. José , Lanas Angel , Abadía-Gallego David , Diez-Fuertes Francisco , Tellería-Orriols Carlos , del-Hoyo-Alonso Rafael , Serrano M. Trinidad
Published: September 2021

Comparing pandemic waves could aid in understanding the evolution of COVID-19. The objective of the present study was to compare the characteristics and outcomes of patients hospitalized for COVID-19 in different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of 5,220 patients hospitalized with SARS-CoV-2 infection from February to September 2020 in Aragon, Spain. We compared ICU admissions and 30-day mortality, clinical characteristics, and risk factors of the first and second waves of COVID-19. The SARS-CoV-2 genome was also analyzed in 236 samples. Patients in the first wave (n = 2,547) were older (median age 74 years [IQR 60–86] vs. 70 years [53–85]; p < 0.001) and had worse clinical and analytical parameters related to severe COVID-19 than patients in the second wave (n = 2,673). The probability of ICU admission at 30 days was 16% and 10% (p < 0.001) and the cumulative 30-day mortality rates 38% and 32% in the first and second wave, respectively (p = 0.007). Survival differences were observed among patients aged 60 to 80 years. We also found some variability among death risk factors and the viral genome between waves. Therefore, the two analyzed COVID-19 pandemic waves were different in terms of disease severity and mortality.
Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension
Authors: Tura-Ceide Olga , Smolders Valérie F. E. D. , Aventin Núria , Morén Constanza , Guitart-Mampel Mariona , Blanco Isabel , Piccari Lucilla , Osorio Jeisson , Rodríguez Cristina , Rigol Montserrat , Solanes Núria , Malandrino Andrea , Kurakula Kondababu , Goumans Marie Jose , Quax Paul H. A. , Peinado Victor I. , Castellà Manuel , Barberà Joan Albert
Published: September 2021

Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.
Activation of EGFR signaling by Tc-Vein and Tc-Spitz regulates the metamorphic transition in the red flour beetle Tribolium castaneum
Authors: Chafino Sílvia , Martín David , Franch-Marro Xavier
Published: September 2021

Animal development relies on a sequence of specific stages that allow the formation of adult structures with a determined size. In general, juvenile stages are dedicated mainly to growth, whereas last stages are devoted predominantly to the maturation of adult structures. In holometabolous insects, metamorphosis marks the end of the growth period as the animals stops feeding and initiate the final differentiation of the tissues. This transition is controlled by the steroid hormone ecdysone produced in the prothoracic gland. InDrosophila melanogasterdifferent signals have been shown to regulate the production of ecdysone, such as PTTH/Torso, TGFß and Egfr signaling. However, to which extent the roles of these signals are conserved remains unknown. Here, we study the role of Egfr signaling in post-embryonic development of the basal holometabolous beetleTribolium castaneum. We show thatTc-Egfr and Tc-pointedare required to induced a proper larval-pupal transition through the control of the expression of ecdysone biosynthetic genes. Furthermore, we identified an additional Tc-Egfr ligand in theTriboliumgenome, the neuregulin-like protein Tc-Vein (Tc-Vn), which contributes to induce larval-pupal transition together with Tc-Spitz (Tc-Spi). Interestingly, we found that in addition to the redundant role in the control of pupa formation, each ligand possesses different functions in organ morphogenesis. Whereas Tc-Spi acts as the main ligand in urogomphi and gin traps, Tc-Vn is required in wings and elytra. Altogether, our findings show that inTribolium, post-embryonic Tc-Egfr signaling activation depends on the presence of two ligands and that its role in metamorphic transition is conserved in holometabolous insects.