bluuebunny/crossref_metadata_2025 huggingface dataset:
Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history
Authors: Yu He , Jamieson Alexandra , Hulme-Beaman Ardern , Conroy Chris J. , Knight Becky , Speller Camilla , Al-Jarah Hiba , Eager Heidi , Trinks Alexandra , Adikari Gamini , Baron Henriette , Böhlendorf-Arslan Beate , Bohingamuwa Wijerathne , Crowther Alison , Cucchi Thomas , Esser Kinie , Fleisher Jeffrey , Gidney Louisa , Gladilina Elena , Gol’din Pavel , Goodman Steven M. , Hamilton-Dyer Sheila , Helm Richard , Hillman Jesse C. , Kallala Nabil , Kivikero Hanna , Kovács Zsófia E. , Kunst Günther Karl , Kyselý René , Linderholm Anna , Maraoui-Telmini Bouthéina , Marković Nemanja , Morales-Muñiz Arturo , Nabais Mariana , O’Connor Terry , Oueslati Tarek , Quintana Morales Eréndira M. , Pasda Kerstin , Perera Jude , Perera Nimal , Radbauer Silvia , Ramon Joan , Rannamäe Eve , Sanmartí Grego Joan , Treasure Edward , Valenzuela-Lamas Silvia , van der Jagt Inge , Van Neer Wim , Vigne Jean-Denis , Walker Thomas , Wynne-Jones Stephanie , Zeiler Jørn , Dobney Keith , Boivin Nicole , Searle Jeremy B. , Krause-Kyora Ben , Krause Johannes , Larson Greger , Orton David
Published: May 2022

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we first generate a de novo genome assembly of the black rat. We then sequence 67 ancient and three modern black rat mitogenomes, and 36 ancient and three modern nuclear genomes from archaeological sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of our newly reported sequences, together with published mitochondrial DNA sequences, confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.
Identification and characterization of a novel enhancer in the HTLV-1 proviral genome
Authors: Matsuo Misaki , Ueno Takaharu , Monde Kazuaki , Sugata Kenji , Tan Benjy Jek Yang , Rahman Akhinur , Miyazato Paola , Uchiyama Kyosuke , Islam Saiful , Katsuya Hiroo , Nakajima Shinsuke , Tokunaga Masahito , Nosaka Kisato , Hata Hiroyuki , Utsunomiya Atae , Fujisawa Jun-ichi , Satou Yorifumi
Published: May 2022

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia/lymphoma (ATL), a cancer of infected CD4+ T-cells. There is both sense and antisense transcription from the integrated provirus. Sense transcription tends to be suppressed, but antisense transcription is constitutively active. Various efforts have been made to elucidate the regulatory mechanism of HTLV-1 provirus for several decades; however, it remains unknown how HTLV-1 antisense transcription is maintained. Here, using proviral DNA-capture sequencing, we found a previously unidentified viral enhancer in the middle of the HTLV-1 provirus. The transcription factors, SRF and ELK-1, play a pivotal role in the activity of this enhancer. Aberrant transcription of genes in the proximity of integration sites was observed in freshly isolated ATL cells. This finding resolves certain long-standing questions concerning HTLV-1 persistence and pathogenesis. We anticipate that the DNA-capture-seq approach can be applied to analyze the regulatory mechanisms of other oncogenic viruses integrated into the host cellular genome.
What sets aeolian dune height?
Authors: Gunn Andrew , Casasanta Giampietro , Di Liberto Luca , Falcini Federico , Lancaster Nicholas , Jerolmack Douglas J.
Published: May 2022

Wherever a loose bed of sand is subject to sufficiently strong winds, aeolian dunes form at predictable wavelengths and growth rates. As dunes mature and coarsen, however, their growth trajectories become more idiosyncratic; nonlinear effects, sediment supply, wind variability and geologic constraints become increasingly relevant, resulting in complex and history-dependent dune amalgamations. Here we examine a fundamental question: do aeolian dunes stop growing and, if so, what determines their ultimate size? Earth’s major sand seas are populated by giant sand dunes, evolved over tens of thousands of years. We perform a global analysis of the topography of these giant dunes, and their associated atmospheric forcings and geologic constraints, and we perform numerical experiments to gain insight on temporal evolution of dune growth. We find no evidence of a previously proposed limit to dune size by atmospheric boundary layer height. Rather, our findings indicate that dunes may grow indefinitely in principle; but growth depends on morphology, slows with increasing size, and may ultimately be limited by sand supply.
Alternative splicing modulation by G-quadruplexes
Authors: Georgakopoulos-Soares Ilias , Parada Guillermo E. , Wong Hei Yuen , Medhi Ragini , Furlan Giulia , Munita Roberto , Miska Eric A. , Kwok Chun Kit , Hemberg Martin
Published: May 2022

Alternative splicing is central to metazoan gene regulation, but the regulatory mechanisms are incompletely understood. Here, we show that G-quadruplex (G4) motifs are enriched ~3-fold near splice junctions. The importance of G4s in RNA is emphasised by a higher enrichment for the non-template strand. RNA-seq data from mouse and human neurons reveals an enrichment of G4s at exons that were skipped following depolarisation induced by potassium chloride. We validate the formation of stable RNA G4s for three candidate splice sites by circular dichroism spectroscopy, UV-melting and fluorescence measurements. Moreover, we find that sQTLs are enriched at G4s, and a minigene experiment provides further support for their role in promoting exon inclusion. Analysis of >1,800 high-throughput experiments reveals multiple RNA binding proteins associated with G4s. Finally, exploration of G4 motifs across eleven species shows strong enrichment at splice sites in mammals and birds, suggesting an evolutionary conserved splice regulatory mechanism.
Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain
Authors: Fan Chun Chieh , Loughnan Robert , Makowski Carolina , Pecheva Diliana , Chen Chi-Hua , Hagler Donald J. , Thompson Wesley K. , Parker Nadine , van der Meer Dennis , Frei Oleksandr , Andreassen Ole A. , Dale Anders M.
Published: May 2022

The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.
A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans
Authors: Onukwufor John O. , Farooqi M. Arsalan , Vodičková Anežka , Koren Shon A. , Baldzizhar Aksana , Berry Brandon J. , Beutner Gisela , Porter George A. , Belousov Vsevolod , Grossfield Alan , Wojtovich Andrew P.
Published: May 2022

C. elegans react to metabolic distress caused by mismatches in oxygen and energy status via distinct behavioral responses. At the molecular level, these responses are coordinated by under-characterized, redox-sensitive processes, thought to initiate in mitochondria. Complex I of the electron transport chain is a major site of reactive oxygen species (ROS) production and is canonically associated with oxidative damage following hypoxic exposure. Here, we use a combination of optogenetics and CRISPR/Cas9-mediated genome editing to exert spatiotemporal control over ROS production. We demonstrate a photo-locomotory remodeling of avoidance behavior by local ROS production due to the reversible oxidation of a single thiol on the complex I subunit NDUF-2.1. Reversible thiol oxidation at this site is necessary and sufficient for the behavioral response to hypoxia, does not respond to ROS produced at more distal sites, and protects against lethal hypoxic exposure. Molecular modeling suggests that oxidation at this thiol residue alters the ability for NDUF-2.1 to coordinate electron transfer to coenzyme Q by destabilizing the Q-binding pocket, causing decreased complex I activity. Overall, site-specific ROS production regulates behavioral responses and these findings provide a mechanistic target to suppress the detrimental effects of hypoxia.
Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism
Authors: Huang Yunpeng , Wan Zhihui , Tang Yinglu , Xu Junxuan , Laboret Bretton , Nallamothu Sree , Yang Chenyu , Liu Boxiang , Lu Rongze Olivia , Lu Bingwei , Feng Juan , Cao Jing , Hayflick Susan , Wu Zhihao , Zhou Bing
Published: May 2022

Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson’s disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.
The representation of context in mouse hippocampus is preserved despite neural drift
Authors: Keinath Alexandra T. , Mosser Coralie-Anne , Brandon Mark P.
Published: May 2022

The hippocampus is thought to mediate episodic memory through the instantiation and reinstatement of context-specific cognitive maps. However, recent longitudinal experiments have challenged this view, reporting that most hippocampal cells change their tuning properties over days even in the same environment. Often referred to as neural or representational drift, these dynamics raise questions about the capacity and content of the hippocampal code. One such question is whether and how these long-term dynamics impact the hippocampal code for context. To address this, we image large CA1 populations over more than a month of daily experience as freely behaving mice participate in an extended geometric morph paradigm. We find that long-timescale changes in population activity occur orthogonally to the representation of context in network space, allowing for consistent readout of contextual information across weeks. This population-level structure is supported by heterogeneous patterns of activity at the level of individual cells, where we observe evidence of a positive relationship between interpretable contextual coding and long-term stability. Together, these results demonstrate that long-timescale changes to the CA1 spatial code preserve the relative structure of contextual representation.
Expanding beaver pond distribution in Arctic Alaska, 1949 to 2019
Authors: Tape Ken D. , Clark Jason A. , Jones Benjamin M. , Kantner Seth , Gaglioti Benjamin V. , Grosse Guido , Nitze Ingmar
Published: May 2022

Beavers were not previously recognized as an Arctic species, and their engineering in the tundra is considered negligible. Recent findings suggest that beavers have moved into Arctic tundra regions and are controlling surface water dynamics, which strongly influence permafrost and landscape stability. Here we use 70 years of satellite images and aerial photography to show the scale and magnitude of northwestward beaver expansion in Alaska, indicated by the construction of over 10,000 beaver ponds in the Arctic tundra. The number of beaver ponds doubled in most areas between ~ 2003 and ~ 2017. Earlier stages of beaver engineering are evident in ~ 1980 imagery, and there is no evidence of beaver engineering in ~ 1952 imagery, consistent with observations from Indigenous communities describing the influx of beavers over the period. Rapidly expanding beaver engineering has created a tundra disturbance regime that appears to be thawing permafrost and exacerbating the effects of climate change.
Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database
Authors: Hoisnard Léa , Lebrun-Vignes Bénédicte , Maury Sébastien , Mahevas Matthieu , El Karoui Khalil , Roy Lydia , Zarour Anissa , Michel Marc , Cohen José L. , Amiot Aurélien , Claudepierre Pascal , Wolkenstein Pierre , Grimbert Philippe , Sbidian Emilie
Published: May 2022

Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports [ICSRs] with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral [herpes and influenza], fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.
Electrical mapping of thermoelectric power factor in WO3 thin film
Authors: Shimizu Sunao , Kishi Tomoya , Ogane Goki , Tokiwa Kazuyasu , Ono Shimpei
Published: May 2022

With growing environmental awareness and considerable research investment in energy saving, the concept of energy harvesting has become a central topic in the field of materials science. The thermoelectric energy conversion, which is a classic physical phenomenon, has emerged as an indispensable thermal management technology. In addition to conventional experimental investigations of thermoelectric materials, seeking promising materials or structures using computer-based approaches such as machine learning has been considered to accelerate research in recent years. However, the tremendous experimental efforts required to evaluate materials may hinder us from reaping the benefits of the fast-developing computer technology. In this study, an electrical mapping of the thermoelectric power factor is performed in a wide temperature-carrier density regime. An ionic gating technique is applied to an oxide semiconductor WO3, systematically controlling the carrier density to induce a transition from an insulating to a metallic state. Upon electrically scanning the thermoelectric properties, it is demonstrated that the thermoelectric performance of WO3 is optimized at a highly degenerate metallic state. This approach is convenient and applicable to a variety of materials, thus prompting the development of novel functional materials with desirable thermoelectric properties.
COVID-19 patient serum less potently inhibits ACE2-RBD binding for various SARS-CoV-2 RBD mutants
Authors: Junker Daniel , Dulovic Alex , Becker Matthias , Wagner Teresa R. , Kaiser Philipp D. , Traenkle Bjoern , Kienzle Katharina , Bunk Stefanie , Struemper Carlotta , Haeberle Helene , Schmauder Kristina , Ruetalo Natalia , Malek Nisar , Althaus Karina , Koeppen Michael , Rothbauer Ulrich , Walz Juliane S. , Schindler Michael , Bitzer Michael , Göpel Siri , Schneiderhan-Marra Nicole
Published: May 2022

As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.
Statistical optimization for simultaneous removal of methyl red and production of fatty acid methyl esters using fresh alga Scenedesmus obliquus
Authors: El‑Naggar Noura El‑Ahmady , Hamouda Ragaa A. , Abou-El-Souod Ghada W.
Published: May 2022

Microalgae are a diverse group of microorganisms, the majority of which are photosynthetic in nature. Microalgae have different applications, the most important of which is the biological treatment of wastewater. Microalgae grow in various types of wastewater, such as wastewater polluted by Azo dyes, due to microalgae using wastewater as a culture medium, which contains many nutrients like nitrogen, phosphate, and carbon sources. Microalgae grow in various types of wastewater, such as wastewater polluted by Azo dyes, due to microalgae using wastewater as a culture medium, which contains many nutrients like nitrogen, phosphate, and carbon sources. So, microalgae are used for bioremediation of wastewater due to the efficiency of growing in wastewater and for the high production of lipids followed by trans-esterification to biodiesel. Face-centered central composite design (FCCCD) was used to determine the factors that have the most significant impact on the simultaneous decolorization of methyl red and lipid production by the fresh green alga Scenedesmus obliquus. The predicted results indicated that the alga decolorized 70.15% methyl red and produced 20.91% lipids by using 1 g/L nitrogen, an incubation time of 10 days, a pH of 8, and the concentration of methyl red is 17.65 mg/L. The dry biomasses of S. obliquus were also examined by SEM and FTIR before and after treatment with methyl red. SEM and FTIR showed that the properties of dry S. obliquus were altered after the biosorption of methyl red. According to GC–MS analysis of hexane extracts of S. obliquus, the lipid profile differed before and after methyl red decolorization. The results proved that it is possible to use S. obliquus to remove dyes and produce renewable fuels such as biodiesel. The novelty of this study is that this is the first time in which the effect of nitrogen concentrations in the medium used for algal growth on the removal of dye has been studied.
Reliability, usability and identified need for home-based cardiometabolic health self-assessment during the COVID-19 pandemic in Soweto, South Africa
Authors: Calvert Clara , Kolkenbeck-Ruh Andrea , Crouch Simone H. , Soepnel Larske M. , Ware Lisa J.
Published: May 2022

A major obstacle to tackling the growing burden of chronic disease in South Africa is lack of testing, particularly where individuals face multiple barriers to accessing health services. We conducted a pilot study to evaluate a cardiometabolic self-measurement kit, including assessment of blood pressure, obesity and urine analysis, amongst adults in Soweto, South Africa. Participants (N = 94) were recruited by researchers during community health screening and were provided with a home test kit including a tablet with self-measurement instructions. The participants entered their results on the tablet and, on completion, the researcher immediately repeated the measurements. We interviewed 10% of participants to understand their experience and views of the kits. Concordance correlation coefficients ranged from 0.78 for waist circumference to 0.93 for height, while the overall percentage agreement ranged from 80.5% for both urine protein and urine glucose testing to 91.4% for the identification of central obesity (ratio of waist circumference to height of ≥ 0.5). Participants saw the need for self-testing and found the process for the most part simple, though urine testing and height self-assessment presented some challenges. This pilot study suggests that self-assessment at home has the potential to facilitate the identification of individuals at risk for cardiometabolic disease in low-income settings, adding to a growing body of evidence on the use of self-testing in disease prevention and detection. However, we would not recommend self-testing for urine glucose and protein without further study.
A network approach to relationships between cannabis use characteristics and psychopathology in the general population
Authors: Betz Linda T. , Penzel Nora , Kambeitz Joseph
Published: May 2022

Cannabis use characteristics, such as earlier initiation and frequent use, have been associated with an increased risk for developing psychotic experiences and psychotic disorders. However, little is known how these characteristics relate to specific aspects of sub-clinical psychopathology in the general population. Here, we explore the relationships between cannabis use characteristics and psychopathology in a large general population sample (N = 2,544, mean age 29.2 years, 47% women) by employing a network approach. This allows for the identification of unique associations between two cannabis use characteristics (lifetime cumulative frequency of cannabis use, age of cannabis use initiation), and specific psychotic experiences and affective symptoms, while controlling for early risk factors (childhood trauma, urban upbringing). We found particularly pronounced unique positive associations between frequency of cannabis use and specific delusional experiences (persecutory delusions and thought broadcasting). Age of cannabis use initiation was negatively related to visual hallucinatory experiences and irritability, implying that these experiences become more likely the earlier use is initiated. Earlier initiation, but not lifetime frequency of cannabis use, was related to early risk factors. These findings suggest that cannabis use characteristics may contribute differentially to risk for specific psychotic experiences and affective symptoms in the general population.
A high-performance compilation strategy for multiplexing quantum control architecture
Authors: Shan Zheng , Zhu Yu , Zhao Bo
Published: May 2022

Quantum computers have already shown significant potential to solve specific problems more efficiently than conventional supercomputers. A major challenge towards noisy intermediate-scale quantum computing is characterizing and reducing the various control costs. Quantum programming describes the process of quantum computation as a sequence, whose elements are selected from a finite set of universal quantum gates. Quantum compilation translates quantum programs to ordered pulses to the quantum control devices subsequently and quantum compilation optimization provides a high-level solution to reduce the control cost efficiently. Here, we propose a high-performance compilation strategy for multiplexing quantum control architecture. For representative benchmarks, the utilization efficiency of control devices increased by 49.44% on average in our work, with an acceptable circuit depth expansion executing on several real superconducting quantum computers of IBM.
Pesticide risk to managed bees during blueberry pollination is primarily driven by off-farm exposures
Authors: Graham Kelsey K. , Milbrath Meghan O. , Zhang Yajun , Baert Nicolas , McArt Scott , Isaacs Rufus
Published: May 2022

When managed bee colonies are brought to farms for crop pollination, they can be exposed to pesticide residues. Quantifying the risk posed by these exposures can indicate which pesticides are of the greatest concern and helps focus efforts to reduce the most harmful exposures. To estimate the risk from pesticides to bees while they are pollinating blueberry fields, we sampled blueberry flowers, foraging bees, pollen collected by returning honey bee and bumble bee foragers at colonies, and wax from honey bee hives in blooming blueberry farms in southwest Michigan. We screened the samples for 261 active ingredients using a modified QuEChERS method. The most abundant pesticides were those applied by blueberry growers during blueberry bloom (e.g., fenbuconazole and methoxyfenozide). However, we also detected highly toxic pesticides not used in this crop during bloom (or other times of the season) including the insecticides chlorpyrifos, clothianidin, avermectin, thiamethoxam, and imidacloprid. Using LD50 values for contact and oral exposure to honey bees and bumble bees, we calculated the Risk Quotient (RQ) for each individual pesticide and the average sample RQ for each farm. RQ values were considered in relation to the U.S. Environmental Protection Agency acute contact level of concern (LOC, 0.4), the European Food Safety Authority (EFSA) acute contact LOC (0.2) and the EFSA chronic oral LOC (0.03). Pollen samples were most likely to exceed LOC values, with the percent of samples above EFSA’s chronic oral LOC being 0% for flowers, 3.4% for whole honey bees, 0% for whole bumble bees, 72.4% for honey bee pollen in 2018, 45.4% of honey bee pollen in 2019, 46.7% of bumble bee pollen in 2019, and 3.5% of honey bee wax samples. Average pollen sample RQ values were above the EFSA chronic LOC in 92.9% of farms in 2018 and 42.9% of farms in 2019 for honey bee collected pollen, and 46.7% of farms for bumble bee collected pollen in 2019. Landscape analyses indicated that sample RQ was positively correlated with the abundance of apple and cherry orchards located within the flight range of the bees, though this varied between bee species and landscape scale. There was no correlation with abundance of blueberry production. Our results highlight the need to mitigate pesticide risk to bees across agricultural landscapes, in addition to focusing on the impact of applications on the farms where they are applied.
In vitro efficacy of essential oils against Sarcoptes scabiei
Authors: Andriantsoanirina Valérie , Guillot Jacques , Ratsimbason Michel , Mekhloufi Ghozlene , Randriamialinoro Faliarivony , Ranarivelo Lalasoanirina , Ariey Frédéric , Durand Rémy
Published: May 2022

The mite Sarcoptes scabiei is responsible for scabies, a pruritic and contagious skin disease in humans. S. scabiei is also responsible for mange in a wide range of animal species. The treatment of S. scabiei infection is hampered by an under-effectiveness of the few available drugs. The objective of this work was to evaluate the in vitro acaricide activity of a large number of plant essential oils (EOs) against S. scabiei. EOs were selected mainly on the basis of traditional treatments for dermatological infections in Madagascar. The sarcoptes originating from a porcine animal model were tested at concentrations ranging from 10 to 0.1%. The viability of sarcoptes was assessed by stereomicroscopic observation at 5 min, 15 min, 30 min, 45 min and then every hour until 6 h after treatment. Estimates of lethal time and lethal concentration producing 50% mortality were generated using a probit analysis. The survival curves were estimated using the Kaplan Meier method. A total of 31 EOs from different plants were tested. Cinnamomum zeylanicum (cinnamom) and Ocimum sanctum (tulsi) oils were the most active for all concentrations tested. They may be included in in vivo studies, in order to further assess their potential interest as topical treatments.
Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics
Authors: Dasgupta Pooja , Mann Anika , Polgar Willma E. , Reinscheid Rainer K. , Zaveri Nurulain T. , Schulz Stefan
Published: May 2022

Multi-receptor targeting has been proposed as a promising strategy for the development of opioid analgesics with fewer side effects. Cebranopadol and AT-121 are prototypical bifunctional ligands targeting the nociceptin/orphanin FQ peptide receptor (NOP) and µ-opioid receptor (MOP) that elicit potent analgesia in humans and nonhuman primates, respectively. Cebranopadol was reported to produce typical MOP-related side effects such as respiratory depression and reward, whereas AT-121 appeared to be devoid of these liabilities. However, the molecular basis underlying different side effect profiles in opioid analgesics remains unknown. Here, we examine agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed MOP/NOP agonists, including cebranopadol and AT-121. We found that these compounds produce strikingly different MOP phosphorylation profiles. Cebranopadol, AT-034 and AT-324 stimulated extensive MOP phosphorylation, whereas AT-201 induced selective phosphorylation at S375 only. AT-121, on the other hand, did not promote any detectable MOP phosphorylation. Conversely, none of these compounds was able to elicit strong NOP phosphorylation and low NOP receptor phosphorylation correlated with partial agonism in a GIRK-channel assay. Our results suggest a close correlation between MOP receptor phosphorylation and side effect profile. Thus, bifunctional MOP/NOP opioid ligands combining low efficacy G protein signaling at both NOP and MOP with no detectable receptor phosphorylation appear to be devoid of side-effects such as respiratory depression, abuse liability or tolerance development, as with AT-121.
About 4-day rhythm of proliferative activity of fibroblast-like cell cultures isn’t endogenous and don’t depend from the variations of Earth’s magnetic field
Authors: Diatroptova Marina A. , Kosyreva Anna M. , Diatroptov Mikhail E.
Published: May 2022

A study of the 4-day rhythm of the proliferative activity of the embryonic fibroblast-like cells in the logarithmic growth phase was carried out. It was shown that in cell cultures obtained on different days from embryos of different ages, the phase of the 4-day rhythm coincides. In vitro the maxima of the proliferative activity were consistent with the minima of the motor activity of mice. Freezing the culture for 2 or 6 days does not cause a shift in the phase of the 4-day rhythm of cell proliferative activity compare with the unfreezing culture. That indicates the existence of an external synchronizer, which determines the 4-day infradian rhythm of the proliferative activity of embryonic cells. Then we daily thawed samples of single L929 culture of mice fibroblast-like cells for 22 and 17 days and researched the dynamics of its proliferative activity. We also showed 4-day rhythm of the simultaneous increase in the number of cells for all thawed samples. Taking into account that deep freezing of a culture leads to the cessation of all life processes, the fact we obtained indicates an exogenous mechanism of the formation of about a 4-day rhythm of the proliferative activity of cell culture. Variations of the Earth's magnetic field could be one of the external synchronizers of the infradian rhythm. We studied the increase in number of L929 cell in conditions of a magnetic permalloy screen and showed that the magnetic shielding no affect the parameters of the infradian rhythm of L929 cell proliferative activity. So further searches of the external synchronizers are need.
Retinal pigment epithelium melanin imaging using polarization-sensitive optical coherence tomography for patients with retinitis pigmentosa
Authors: Sakai Daiki , Takagi Seiji , Totani Kota , Yamamoto Midori , Matsuzaki Mitsuhiro , Yamanari Masahiro , Sugiyama Satoshi , Yokota Satoshi , Maeda Akiko , Hirami Yasuhiko , Mandai Michiko , Takahashi Masayo , Nakamura Makoto , Kurimoto Yasuo
Published: May 2022

This study aimed to evaluate the distribution of retinal pigment epithelium (RPE) melanin in patients with retinitis pigmentosa (RP) using entropy measurements by custom-made polarization-sensitive optical coherence tomography (PS-OCT) images, and compare entropy with the intensity of short-wavelength (SW) and near-infrared (NIR) autofluorescence (AF). We retrospectively reviewed the retinal images, including PS-OCT, SW-AF, and NIR-AF of patients with RP who had a hyperautofluorescent ring on AF. A total of 12 eyes of 12 patients (8 women and 4 men; mean age: 37.9 years) were included. There was a strong positive correlation between entropy value and NIR-AF intensity (r = 0.626, p < 0.001), and there was a very weak negative correlation between entropy value and SW-AF (r = − 0.197, p = 0.001). The mean values of the entropy in the foveal, temporal (2 mm from the fovea), and nasal (2 mm from the fovea) sections were 0.41 (± 0.09), 0.29 (± 0.08), and 0.26 (± 0.08), respectively. The entropy was significantly higher in the foveal section than in the temporal and nasal sections (p = 0.002 and p = 0.003, respectively). There was no significant difference between the entropies values for the temporal and nasal sections (p = 0.157). Age, logMAR best-corrected visual acuity, ellipsoid zone width, and central retinal thickness were not correlated with foveal entropy. We presented RPE melanin imaging in patients with RP using PS-OCT for the first time. PS-OCT can be a useful tool for monitoring patients with RP.
High-sensitivity C-reactive protein could be a potential indicator of bone mineral density in adolescents aged 10–20 years
Authors: Ye Weiran , Cheng Shi , Xiao Jin , Yu Hui
Published: May 2022

There was very limited evidence linking high-sensitivity C-reactive protein (HS-CRP) and total bone mineral density (BMD) in adolescents. The aim of this population-based study was to investigate the relationship between HS-CRP and total BMD in adolescents aged 10–20 years. A cross-sectional study was performed in the normal U.S. population from the data of the National Health and Nutrition Examination Survey (NHANES). The correlation between HS-CRP and total BMD was evaluated by using weighted multivariate linear regression models. And further subgroup analysis was conducted. There were 1747 participants in this study, 47.1% were female, 29.4% were white, 19.5% were black, and 22.3% were Mexican–American. In the multi-regression model that after the potential confounders had been adjusted, HS-CRP was negatively associated with total BMD. The negative association was also observed in the subgroup analyses stratified by gender and age. Our results demonstrated that higher HS-CRP was negatively correlated with total BMD in 10–20 years old adolescents.
Circulating microRNA sequencing revealed miRNome patterns in hematology and oncology patients aiding the prognosis of invasive aspergillosis
Authors: Fidler Gábor , Szilágyi-Rácz Anna Anita , Dávid Péter , Tolnai Emese , Rejtő László , Szász Róbert , Póliska Szilárd , Biró Sándor , Paholcsek Melinda
Published: May 2022

Invasive aspergillosis (IA) may occur as a serious complication of hematological malignancy. Delays in antifungal therapy can lead to an invasive disease resulting in high mortality. Currently, there are no well-established blood circulating microRNA biomarkers or laboratory tests which can be used to diagnose IA. Therefore, we aimed to define dysregulated miRNAs in hematology and oncology (HO) patients to identify biomarkers predisposing disease. We performed an in-depth analysis of high-throughput small transcriptome sequencing data obtained from the whole blood samples of our study cohort of 50 participants including 26 high-risk HO patients and 24 controls. By integrating in silico bioinformatic analyses of small noncoding RNA data, 57 miRNAs exhibiting significant expression differences (P < 0.05) were identified between IA-infected patients and non-IA HO patients. Among these, we found 36 differentially expressed miRNAs (DEMs) irrespective of HO malignancy. Of the top ranked DEMs, we found 14 significantly deregulated miRNAs, whose expression levels were successfully quantified by qRT-PCR. MiRNA target prediction revealed the involvement of IA related miRNAs in the biological pathways of tumorigenesis, the cell cycle, the immune response, cell differentiation and apoptosis.
Mutagenicity and safety pharmacology of a standardized antidiabetic polyherbal formulation
Authors: Abdul Majid Fadzilah Adibah , Fadhlina Anis , Ismail Hassan Fahmi , Zainol Siti Nurazwa , Mamillapalli Archan Kumar , Venkatesan Vijayabalaji , Eswarappa Rajesh , Pillai Renuka
Published: May 2022

Synacinn is a standardized polyherbal extract formulated for the treatment of diabetes mellitus and its complications. This study aims to assess the mutagenicity potential of Synacinn by Ames assay and in vivo bone marrow micronucleus (MN) test on Sprague Dawley rat. Human ether-a-go-go-related gene (hERG) assay and Functional Observation Battery (FOB) were done for the safety pharmacology tests. In the Ames assay, Dose Range Finding (DRF) study and mutagenicity assays (+/− S9) were carried out. For the MN test, a preliminary and definitive study were conducted. In-life observations and number of immature and mature erythrocytes in the bone marrow cells were recorded. The hERG assay was conducted to determine the inhibitory effect on hERG potassium channel current expressed in human embryonic kidney cells (HEK293). FOB tests were performed orally (250, 750, and 2000 mg/kg) on Sprague Dawley rats. Synacinn is non-mutagenic against all tested strains of Salmonella typhimurium and did not induce any clastogenicity in the rat bone marrow. Synacinn also did not produce any significant inhibition (p ≤ 0.05) on hERG potassium current. Synacinn did not cause any neurobehavioural changes in rats up to 2000 mg/kg. Thus, no mutagenicity, cardiotoxicity and neurotoxicity effects of Synacinn were observed in this study.
Whole genome sequencing of multidrug-resistant Mycobacterium tuberculosis isolates collected in the Czech Republic, 2005–2020
Authors: Dohál Matúš , Dvořáková Věra , Šperková Miluše , Pinková Martina , Spitaleri Andrea , Norman Anders , Cabibbe Andrea Maurizio , Rasmussen Erik Michael , Porvazník Igor , Škereňová Mária , Solovič Ivan , Cirillo Daniela Maria , Mokrý Juraj
Published: May 2022

The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005–2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.
Comparison of blood pool and myocardial 3D printing in the diagnosis of types of congenital heart disease
Authors: Liang Jixiang , Zhao Xin , Pan Guangyu , Zhang Gen , Zhao Dianjiang , Xu Jianping , Li Dianyuan , Lu Bingheng
Published: May 2022

The study aimed to evaluate the effectiveness of blood pool and myocardial models made by stereolithography in the diagnosis of different types of congenital heart disease (CHD). Two modeling methods were applied in the diagnosis of 8 cases, and two control groups consisting of experts and students diagnosed the cases using echocardiography with computed tomography, blood pool models, and myocardial models. The importance, suitability, and simulation degree of different models were analyzed. The average diagnostic rate before and after 3D printing was used was 88.75% and 95.9% (P = 0.001) in the expert group and 60% and 91.6% (P = 0.000) in the student group, respectively. 3D printing was considered to be more important for the diagnosis of complex CHDs (very important; average, 87.8%) than simple CHDs (very important; average, 30.8%) (P = 0.000). Myocardial models were considered most realistic regarding the structure of the heart (average, 92.5%). In cases of congenital corrected transposition of great arteries, Williams syndrome, coronary artery fistula, tetralogy of Fallot, patent ductus arteriosus, and coarctation of the aorta, blood pool models were considered more effective (average, 92.1%), while in cases of double outlet right ventricle and ventricular septal defect, myocardial models were considered optimal (average, 80%).
A comparison of strategies for generating artificial replicates in RNA-seq experiments
Authors: Saremi Babak , Gusmag Frederic , Distl Ottmar , Schaarschmidt Frank , Metzger Julia , Becker Stefanie , Jung Klaus
Published: May 2022

Due to the overall high costs, technical replicates are usually omitted in RNA-seq experiments, but several methods exist to generate them artificially. Bootstrapping reads from FASTQ-files has recently been used in the context of other NGS analyses and can be used to generate artificial technical replicates. Bootstrapping samples from the columns of the expression matrix has already been used for DNA microarray data and generates a new artificial replicate of the whole experiment. Mixing data of individual samples has been used for data augmentation in machine learning. The aim of this comparison is to evaluate which of these strategies are best suited to study the reproducibility of differential expression and gene-set enrichment analysis in an RNA-seq experiment. To study the approaches under controlled conditions, we performed a new RNA-seq experiment on gene expression changes upon virus infection compared to untreated control samples. In order to compare the approaches for artificial replicates, each of the samples was sequenced twice, i.e. as true technical replicates, and differential expression analysis and GO term enrichment analysis was conducted separately for the two resulting data sets. Although we observed a high correlation between the results from the two replicates, there are still many genes and GO terms that would be selected from one replicate but not from the other. Cluster analyses showed that artificial replicates generated by bootstrapping reads produce it p values and fold changes that are close to those obtained from the true data sets. Results generated from artificial replicates with the approaches of column bootstrap or mixing observations were less similar to the results from the true replicates. Furthermore, the overlap of results among replicates generated by column bootstrap or mixing observations was much stronger than among the true replicates. Artificial technical replicates generated by bootstrapping sequencing reads from FASTQ-files are better suited to study the reproducibility of results from differential expression and GO term enrichment analysis in RNA-seq experiments than column bootstrap or mixing observations. However, FASTQ-bootstrapping is computationally more expensive than the other two approaches. The FASTQ-bootstrapping may be applicable to other applications of high-throughput sequencing.
Investigation and validation of labelling loop mediated isothermal amplification (LAMP) products with different nucleotide modifications for various downstream analysis
Authors: Warmt Christian , Yaslanmaz Ceren , Henkel Jörg
Published: May 2022

Loop mediated isothermal amplification (LAMP) is one of the best known and most popular isothermal amplification methods. It's simplicity and speed make the method particularly suitable for point-of-care diagnostics. Nevertheless, false positive results remain a major drawback. Many (downstream) applications are known for the detection of LAMP amplicons like colorimetric assays, in-situ LAMP or CRISPR-Cas systems. Often, modifications of the LAMP products are necessary for different detection applications such as lateral flow assays. This is usually achieved with pre-modified primer. The aim of this study is to evaluate amplicon labelling with different modified nucleotides such as Cy5-dUTP, biotin-dUTP and aminoallyl-dUTP as an alternative to pre-labelled primers. To realise this, the effects on amplification and labelling efficiency were studied as a function of molecule size and nucleotide amount as well as target concentration. This research shows that diverse labelling of LAMP amplicons can be achieved using different, modified nucleotides during LAMP and that these samples can be analysed by a wide range of downstream applications such as fluorescence spectroscopy, gel electrophoresis, microarrays and lateral flow systems. Furthermore, microarray-based detection and the ability to identify and distinguish false positives were demonstrated as proof of concept.