bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimisation of a TALE nuclease targeting the HIV co-receptor CCR5 for clinical application
Authors: Schwarze Lea Isabell , Głów Dawid , Sonntag Tanja , Uhde Almut , Fehse Boris
Published: June 2021

Disruption of theC-C-Chemokine-receptor-5(CCR5) gene induces resistance towards CCR5-tropic HIV. Here we optimised our previously described CCR5-Uco-TALEN and its delivery by mRNA electroporation. The novel variant, CCR5-Uco-hetTALEN features an obligatory heterodimeric Fok1-cleavage domain, which resulted in complete abrogation of off-target activity at previously found homodimeric as well as 7/8 in silico predicted, potential heterodimeric off-target sites, the only exception being highly homologousCCR2. Prevailing 18- and 10-bp deletions at the on-target site revealed microhomology-mediated end-joining as a major repair pathway. Notably, the CCR5Δ55–60protein resulting from the 18-bp deletion was almost completely retained in the cytosol. Simultaneous cutting atCCR5andCCR2induced rearrangements, mainly 15-kb deletions between the cut sites, in up to 2% of T cells underlining the necessity to restrict TALEN expression. We optimised in vitro mRNA production and showed thatCCR5-on- andCCR2off-target activities of CCR5-Uco-hetTALEN were limited to the first 72 and 24–48 h post-mRNA electroporation, respectively. Using single-cell HRMCA, we discovered high rates of TALEN-induced biallelic gene editing ofCCR5, which translated in large numbers of CCR5-negative cells resistant to HIVenv-pseudotyped lentiviral vectors. We conclude that CCR5-Uco-hetTALEN transfected by mRNA electroporation facilitates specific, high-efficiencyCCR5gene-editing (30%–56%) and it is highly suited for clinical translation subject to further characterisation of off-target effects.
E2F6 initiates stable epigenetic silencing of germline genes during embryonic development
Authors: Dahlet Thomas , Truss Matthias , Frede Ute , Al Adhami Hala , Bardet Anaïs F. , Dumas Michael , Vallet Judith , Chicher Johana , Hammann Philippe , Kottnik Sarah , Hansen Peter , Luz Uschi , Alvarez Gonzalo , Auclair Ghislain , Hecht Jochen , Robinson Peter N. , Hagemeier Christian , Weber Michael
Published: June 2021

In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development.
The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals an Arpp19/PP2A-B55 feedback loop
Authors: Labbé Jean Claude , Vigneron Suzanne , Méchali Francisca , Robert Perle , Roque Sylvain , Genoud Cindy , Goguet-Rubio Perrine , Barthe Phillipe , Labesse Gilles , Cohen-Gonsaud Martin , Castro Anna , Lorca Thierry
Published: June 2021

Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as a competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signalling mechanism is elusive. Here, we characterize the molecular determinants conferring high affinity and slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we show that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discover a double feed-back loop between these two phospho-sites essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.
Reliable identification of protein-protein interactions by crosslinking mass spectrometry
Authors: Lenz Swantje , Sinn Ludwig R. , O’Reilly Francis J. , Fischer Lutz , Wegner Fritz , Rappsilber Juri
Published: June 2021

Protein-protein interactions govern most cellular pathways and processes, and multiple technologies have emerged to systematically map them. Assessing the error of interaction networks has been a challenge. Crosslinking mass spectrometry is currently widening its scope from structural analyses of purified multi-protein complexes towards systems-wide analyses of protein-protein interactions (PPIs). Using a carefully controlled large-scale analysis of Escherichia coli cell lysate, we demonstrate that false-discovery rates (FDR) for PPIs identified by crosslinking mass spectrometry can be reliably estimated. We present an interaction network comprising 590 PPIs at 1% decoy-based PPI-FDR. The structural information included in this network localises the binding site of the hitherto uncharacterised protein YacL to near the DNA exit tunnel on the RNA polymerase.
Highly sensitive active pixel image sensor array driven by large-area bilayer MoS2 transistor circuitry
Authors: Hong Seongin , Zagni Nicolò , Choo Sooho , Liu Na , Baek Seungho , Bala Arindam , Yoo Hocheon , Kang Byung Ha , Kim Hyun Jae , Yun Hyung Joong , Alam Muhammad Ashraful , Kim Sunkook
Published: June 2021

Various large-area growth methods for two-dimensional transition metal dichalcogenides have been developed recently for future electronic and photonic applications. However, they have not yet been employed for synthesizing active pixel image sensors. Here, we report on an active pixel image sensor array with a bilayer MoS2 film prepared via a two-step large-area growth method. The active pixel of image sensor is composed of 2D MoS2 switching transistors and 2D MoS2 phototransistors. The maximum photoresponsivity (Rph) of the bilayer MoS2 phototransistors in an 8 × 8 active pixel image sensor array is statistically measured as high as 119.16 A W−1. With the aid of computational modeling, we find that the main mechanism for the high Rph of the bilayer MoS2 phototransistor is a photo-gating effect by the holes trapped at subgap states. The image-sensing characteristics of the bilayer MoS2 active pixel image sensor array are successfully investigated using light stencil projection.
Electromagnetic power of lightning superbolts from Earth to space
Authors: Ripoll J.-F. , Farges T. , Malaspina D. M. , Cunningham G. S. , Lay E. H. , Hospodarsky G. B. , Kletzing C. A. , Wygant J. R. , Pédeboy S.
Published: June 2021

Lightning superbolts are the most powerful and rare lightning events with intense optical emission, first identified from space. Superbolt events occurred in 2010-2018 could be localized by extracting the high energy tail of the lightning stroke signals measured by the very low frequency ground stations of the World-Wide Lightning Location Network. Here, we report electromagnetic observations of superbolts from space using Van Allen Probes satellite measurements, and ground measurements, and with two events measured both from ground and space. From burst-triggered measurements, we compute electric and magnetic power spectral density for very low frequency waves driven by superbolts, both on Earth and transmitted into space, demonstrating that superbolts transmit 10-1000 times more powerful very low frequency waves into space than typical strokes and revealing that their extreme nature is observed in space. We find several properties of superbolts that notably differ from most lightning flashes; a more symmetric first ground-wave peak due to a longer rise time, larger peak current, weaker decay of electromagnetic power density in space with distance, and a power mostly confined in the very low frequency range. Their signal is absent in space during day times and is received with a long-time delay on the Van Allen Probes. These results have implications for our understanding of lightning and superbolts, for ionosphere-magnetosphere wave transmission, wave propagation in space, and remote sensing of extreme events.
Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
Authors: Cullen Nicholas C. , Leuzy Antoine , Janelidze Shorena , Palmqvist Sebastian , Svenningsson Anna L. , Stomrud Erik , Dage Jeffrey L. , Mattsson-Carlgren Niklas , Hansson Oskar
Published: June 2021

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer’s Clinical Composite; R2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77–0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54–81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53–70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
Adherence to public institutions that foster cooperation
Authors: Radzvilavicius Arunas L. , Kessinger Taylor A. , Plotkin Joshua B.
Published: June 2021

Humans typically consider altruism a moral good and condition their social behavior on the moral reputations of others. Indirect reciprocity explains how social norms and reputations support cooperation: individuals cooperate with others who are considered good. Indirect reciprocity works when an institution monitors and publicly broadcasts moral reputations. Here we develop a theory of adherence to public monitoring in societies where individuals are, at first, independently responsible for evaluating the reputations of their peers. Using a mathematical model, we show that adherence to an institution of moral assessment can evolve and promote cooperation under four different social norms, including norms that previous studies found to perform poorly. We determine how an institution’s size and its degree of tolerance towards anti-social behavior affect the rate of cooperation. Public monitoring serves to eliminate disagreements about reputations, which increases cooperation and payoffs, so that adherence evolves by social contagion and remains robust against displacement.
A design strategy for high mobility stretchable polymer semiconductors
Authors: Mun Jaewan , Ochiai Yuto , Wang Weichen , Zheng Yu , Zheng Yu-Qing , Wu Hung-Chin , Matsuhisa Naoji , Higashihara Tomoya , Tok Jeffrey B.-H. , Yun Youngjun , Bao Zhenan
Published: June 2021

As a key component in stretchable electronics, semiconducting polymers have been widely studied. However, it remains challenging to achieve stretchable semiconducting polymers with high mobility and mechanical reversibility against repeated mechanical stress. Here, we report a simple and universal strategy to realize intrinsically stretchable semiconducting polymers with controlled multi-scale ordering to address this challenge. Specifically, incorporating two types of randomly distributed co-monomer units reduces overall crystallinity and longer-range orders while maintaining short-range ordered aggregates. The resulting polymers maintain high mobility while having much improved stretchability and mechanical reversibility compared with the regular polymer structure with only one type of co-monomer units. Interestingly, the crystalline microstructures are mostly retained even under strain, which may contribute to the improved robustness of our stretchable semiconductors. The proposed molecular design concept is observed to improve the mechanical properties of various p- and n-type conjugated polymers, thus showing the general applicability of our approach. Finally, fully stretchable transistors fabricated with our newly designed stretchable semiconductors exhibit the highest and most stable mobility retention capability under repeated strains of 1,000 cycles. Our general molecular engineering strategy offers a rapid way to develop high mobility stretchable semiconducting polymers.
Dynamic self-assembly of compartmentalized DNA nanotubes
Authors: Agarwal Siddharth , Klocke Melissa A. , Pungchai Passa E. , Franco Elisa
Published: June 2021

Bottom-up synthetic biology aims to engineer artificial cells capable of responsive behaviors by using a minimal set of molecular components. An important challenge toward this goal is the development of programmable biomaterials that can provide active spatial organization in cell-sized compartments. Here, we demonstrate the dynamic self-assembly of nucleic acid (NA) nanotubes inside water-in-oil droplets. We develop methods to encapsulate and assemble different types of DNA nanotubes from programmable DNA monomers, and demonstrate temporal control of assembly via designed pathways of RNA production and degradation. We examine the dynamic response of encapsulated nanotube assembly and disassembly with the support of statistical analysis of droplet images. Our study provides a toolkit of methods and components to build increasingly complex and functional NA materials to mimic life-like functions in synthetic cells.
Effect of specific non-pharmaceutical intervention policies on SARS-CoV-2 transmission in the counties of the United States
Authors: Yang Bingyi , Huang Angkana T. , Garcia-Carreras Bernardo , Hart William E. , Staid Andrea , Hitchings Matt D. T. , Lee Elizabeth C. , Howe Chanelle J. , Grantz Kyra H. , Wesolowksi Amy , Lemaitre Joseph Chadi , Rattigan Susan , Moreno Carlos , Borgert Brooke A. , Dale Celeste , Quigley Nicole , Cummings Andrew , McLorg Alizée , LoMonaco Kaelene , Schlossberg Sarah , Barron-Kraus Drew , Shrock Harrison ,   UFCOVID Interventions Team, Khoury Stephanie , Indra Meenal , Yau Hung-Leong , Cummings Ben , Giannas Peter , McLean Martha-Grace , Hubbard Ken , Saunders Camazia , Weldon Caroline , Phillips Caroline , Rosenbaum David , Tabla Dianelys , Lessler Justin , Laird Carl D. , Cummings Derek A. T.
Published: June 2021

Non-pharmaceutical interventions (NPIs) remain the only widely available tool for controlling the ongoing SARS-CoV-2 pandemic. We estimated weekly values of the effective basic reproductive number (Reff) using a mechanistic metapopulation model and associated these with county-level characteristics and NPIs in the United States (US). Interventions that included school and leisure activities closure and nursing home visiting bans were all associated with a median Reffbelow 1 when combined with either stay at home orders (median Reff0.97, 95% confidence interval (CI) 0.58–1.39) or face masks (median Reff0.97, 95% CI 0.58–1.39). While direct causal effects of interventions remain unclear, our results suggest that relaxation of some NPIs will need to be counterbalanced by continuation and/or implementation of others.
SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung
Authors: Routhu Nanda Kishore , Cheedarla Narayanaiah , Bollimpelli Venkata Satish , Gangadhara Sailaja , Edara Venkata Viswanadh , Lai Lilin , Sahoo Anusmita , Shiferaw Ayalnesh , Styles Tiffany M. , Floyd Katharine , Fischinger Stephanie , Atyeo Caroline , Shin Sally A. , Gumber Sanjeev , Kirejczyk Shannon , Dinnon Kenneth H. , Shi Pei-Yong , Menachery Vineet D. , Tomai Mark , Fox Christopher B. , Alter Galit , Vanderford Thomas H. , Gralinski Lisa , Suthar Mehul S. , Amara Rama Rao
Published: June 2021

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.
Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study
Authors: Li Na , Lim Belle W. X. , Thompson Ella R. , McInerny Simone , Zethoven Magnus , Cheasley Dane , Rowley Simone M. , Wong-Brown Michelle W. , Devereux Lisa , Gorringe Kylie L. , Sloan Erica K. , Trainer Alison , Scott Rodney J. , James Paul A. , Campbell Ian G.
Published: June 2021

Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyondBRCA1andBRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution ofATM,PALB2andCHEK2to BC predisposition was confirmed, but notRAD50andNBN. An overall excess of loss-of-function (LoF) (OR 1.27,p = 9.05 × 10−9) and missense (OR 1.27,p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study includeNTHL1,WRN,PARP2,CTHandCDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
Impact of dose-dense neoadjuvant chemotherapy on pathologic response and survival for HER2-positive breast cancer patients who receive trastuzumab
Authors: Wang Lize , Zhang Yang , He Yingjian , Li Jinfeng , Wang Tianfeng , Xie Yuntao , Fan Zhaoqing , Ouyang Tao
Published: June 2021

To compare outcomes in patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer who received either dose-dense neoadjuvant chemotherapy (NAC) with trastuzumab or standard-interval chemotherapy with trastuzumab. Patients with HER2-positive breast cancer who received NAC, including epirubicin and cyclophosphamide followed by paclitaxel with trastuzumab were included. Patients were divided into either the dose-dense or standard-interval group. We compared pathologic complete remission (pCR), distant disease-free survival (DDFS), event-free survival (EFS), and breast cancer-specific survival (BCSS) between the two groups. Two hundred (49.6%) patients received dose-dense NAC, and 203 (50.4%) received standard-interval NAC. The pCR rate was 38.4% in the dose-dense group and 29.2% in the standard-interval group (P = 0.052). In patients with lymph node (LN) metastases, the LN pCR rate was 70.9% in the dose-dense group and 56.5% in the standard-interval group (P = 0.037). After a median follow-up of 54.6 months, dose-dense chemotherapy presented an improvement on DDFS (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.19–1.28, EFS (HR = 0.54, 95% CI: 0.24–1.21), and BCSS (HR = 0.41, 95% CI: 0.11–1.51), but the difference was not significant. Compared with standard-interval chemotherapy, dose-dense chemotherapy resulted in a superior 5-year DDFS (100% vs. 75.3%, P = 0.017) and 5-year EFS (96.9% vs. 78.3%, P = 0.022) in patients younger than 40 years. HER2-positive patients can achieve a higher LN pCR rate with dose-dense NAC than with standard-interval NAC with trastuzumab. Better survival may also be achieved with dose-dense chemotherapy with trastuzumab than with standard-interval chemotherapy with trastuzumab among young patients (age ≤ 40 years).
Permutable SOS (symmetry operational similarity)
Authors: Cheong Sang-Wook , Lim Seongjoon , Du Kai , Huang Fei-Ting
Published: June 2021

Based on symmetry consideration, quasi-one-dimensional (1D) objects, relevant to numerous observables or phenomena, can be classified into eight different types. We provide various examples of each 1D type and discuss their symmetry operational similarity (SOS) relationships, which are often permutable. A number of recent experimental observations, including current-induced magnetization in polar or chiral conductors, non-linear Hall effect in polar conductors, spin-polarization of tunneling current to chiral conductors, and ferro-rotational domain imaging with linear gyration are discussed in terms of (permutable) SOS. In addition, based on (permutable) SOS, we predict a large number of new phenomena in low symmetry materials that can be experimentally verified in the future.
Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER
Authors: Barberis Matteo
Published: June 2021

In budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A “clock unit” incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This “clock unit” may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.
An open tool for creating battery-electric vehicle time series from empirical data, emobpy
Authors: Gaete-Morales Carlos , Kramer Hendrik , Schill Wolf-Peter , Zerrahn Alexander
Published: June 2021

There is substantial research interest in how future fleets of battery-electric vehicles will interact with the power sector. Various types of energy models are used for respective analyses. They depend on meaningful input parameters, in particular time series of vehicle mobility, driving electricity consumption, grid availability, or grid electricity demand. As the availability of such data is highly limited, we introduce the open-source tool emobpy. Based on mobility statistics, physical properties of battery-electric vehicles, and other customizable assumptions, it derives time series data that can readily be used in a wide range of model applications. For an illustration, we create and characterize 200 vehicle profiles for Germany. Depending on the hour of the day, a fleet of one million vehicles has a median grid availability between 5 and 7 gigawatts, as vehicles are parking most of the time. Four exemplary grid electricity demand time series illustrate the smoothing effect of balanced charging strategies.
Environmental and diagenetic controls on the morphology and calcification of the Ediacaran metazoan Cloudina
Authors: Shore Amy , Wood Rachel
Published: June 2021

Cloudina is a globally distributed Ediacaran metazoan, with a tubular, funnel-in-funnel form built of thin laminae (ca. 1–10 μm). To what degree local environmental controlled morphology, and whether early diagenesis controlled the degree of calcification of Cloudina, is debated. Here we test these hypotheses by considering assemblages from four, coeval localities from the Upper Omkyk Member, Nama Group, Namibia, from inner ramp to mid-ramp reef across the Zaris Subbasin. We show that sinuosity of the Cloudina tube is variable between sites, as is the relative thickness of the tube wall, suggesting these features were environmentally controlled. Walls are thickest in high-energy reef settings, and thinnest in the low-energy, inner ramp. While local diagenesis controls preservation, all diagenetic expressions are consistent with the presence of weakly calcified, organic-rich laminae, and lamina thicknesses are broadly constant. Finally, internal ‘cements’ within Cloudina are found in all sites, and pre-date skeletal breakage, transport, as well as syn-sedimentary botryoidal cement precipitation. Best preservation shows these to be formed by fine, pseudomorphed aragonitic acicular crystals. Sr concentrations and Mg/Ca show no statistically significant differences between internal Cloudina cements and botryoidal cements, but we infer all internal cements to have precipitated when Cloudina was still in-situ and added considerable mechanical strength, but may have formed post-mortem or in abandoned parts of the skeleton.
Allele frequencies of single nucleotide polymorphisms of clinically important drug-metabolizing enzymes CYP2C9, CYP2C19, and CYP3A4 in a Thai population
Authors: Sukprasong Rattanaporn , Chuwongwattana Sumonrat , Koomdee Napatrupron , Jantararoungtong Thawinee , Prommas Santirhat , Jinda Pimonpan , Rachanakul Jiratha , Nuntharadthanaphong Nutthan , Jongjitsook Nutcha , Puangpetch Apichaya , Sukasem Chonlaphat
Published: June 2021

Prior knowledge of allele frequencies of cytochrome P450 polymorphisms in a population is crucial for the revision and optimization of existing medication choices and doses. In the current study, the frequency of theCYP2C9*2,CYP2C9*3,CYP2C19*2,CYP2C19*3,CYP2C19*6,CYP2C19*17, andCYP3A4(rs4646437) alleles in a Thai population across different regions of Thailand was examined. Tests for polymorphisms ofCYP2C9andCYP3A4were performed using TaqMan SNP genotyping assay andCYP2C19was performed using two different methods; TaqMan SNP genotyping assay and Luminex x Tag V3. The blood samples were collected from 1205 unrelated healthy individuals across different regions within Thailand. Polymorphisms ofCYP2C9andCYP2C19were transformed into phenotypes, which included normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid metabolizers (RM). TheCYP2C9allele frequencies among the Thai population were 0.08% and 5.27% for theCYP2C9*2andCYP2C9*3alleles, respectively. TheCYP2C19allele frequencies among the Thai population were 25.60%, 2.50%, 0.10%, and 1.80% for theCYP2C19*2,CYP2C19*3,CYP2C19*6, andCYP2C19*17alleles, respectively. The allele frequency of theCYP3A4(rs4646437) variant allele was 28.50% in the Thai population. The frequency of theCYP2C9*3allele was significantly lower among the Northern Thai population (P < 0.001). The frequency of theCYP2C19*17allele was significantly higher in the Southern Thai population (P < 0.001). Our results may provide an understanding of the ethnic differences in drug responses and support for the utilization of pharmacogenomics testing in clinical practice.
Drug target gene-based analyses of drug repositionability in rare and intractable diseases
Authors: Sakate Ryuichi , Kimura Tomonori
Published: June 2021

Drug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We aimed to analyze the trend of drug repositioning and inter-disease drug repositionability among rare and intractable diseases. We created a list of rare and intractable diseases based on the designated diseases in Japan. Drug information extracted from clinical trial data were integrated with information of drug target genes, which represent the mechanism of drug action. We obtained 753 drugs and 551 drug target genes from 8307 clinical trials for 189 diseases or disease groups. Trend analysis of drug sharing between a disease pair revealed that 1676 drug repositioning events occurred in 4401 disease pairs. A score, Rgene, was invented to investigate the proportion of drug target genes shared between a disease pair. Annual changes of Rgene corresponded to the trend of drug repositioning and predicted drug repositioning events occurring within a year or two. Drug target gene-based analyses well visualized the drug repositioning landscape. This approach facilitates drug development for rare and intractable diseases.
An integrative investigation of sensory organ development and orientation behavior throughout the larval phase of a coral reef fish
Authors: Majoris John E. , Foretich Matthew A. , Hu Yinan , Nickles Katie R. , Di Persia Camilla L. , Chaput Romain , Schlatter E. , Webb Jacqueline F. , Paris Claire B. , Buston Peter M.
Published: June 2021

The dispersal of marine larvae determines the level of connectivity among populations, influences population dynamics, and affects evolutionary processes. Patterns of dispersal are influenced by both ocean currents and larval behavior, yet the role of behavior remains poorly understood. Here we report the first integrated study of the ontogeny of multiple sensory systems and orientation behavior throughout the larval phase of a coral reef fish—the neon goby, Elacatinus lori. We document the developmental morphology of all major sensory organs (lateral line, visual, auditory, olfactory, gustatory) together with the development of larval swimming and orientation behaviors observed in a circular arena set adrift at sea. We show that all sensory organs are present at hatch and increase in size (or number) and complexity throughout the larval phase. Further, we demonstrate that most larvae can orient as early as 2 days post-hatch, and they swim faster and straighter as they develop. We conclude that sensory organs and swimming abilities are sufficiently developed to allow E. lori larvae to orient soon after hatch, suggesting that early orientation behavior may be common among coral reef fishes. Finally, we provide a framework for testing alternative hypotheses for the orientation strategies used by fish larvae, laying a foundation for a deeper understanding of the role of behavior in shaping dispersal patterns in the sea.
Tailored generation of insulin producing cells from canine mesenchymal stem cells derived from bone marrow and adipose tissue
Authors: Rodprasert Watchareewan , Nantavisai Sirirat , Pathanachai Koranis , Pavasant Prasit , Osathanon Thanaphum , Sawangmake Chenphop
Published: June 2021

The trend of regenerative therapy for diabetes in human and veterinary practices has conceptually been proven according to the Edmonton protocol and animal models. Establishing an alternative insulin-producing cell (IPC) resource for further clinical application is a challenging task. This study investigated IPC generation from two practical canine mesenchymal stem cells (cMSCs), canine bone marrow-derived MSCs (cBM-MSCs) and canine adipose-derived MSCs (cAD-MSCs). The results illustrated that cBM-MSCs and cAD-MSCs contain distinct pancreatic differentiation potential and require the tailor-made induction protocols. The effective generation of cBM-MSC-derived IPCs needs the integration of genetic and microenvironment manipulation using a hanging-drop culture ofPDX1-transfected cBM-MSCs under a three-step pancreatic induction protocol. However, this protocol is resource- and time-consuming. Another study on cAD-MSC-derived IPC generation found that IPC colonies could be obtained by a low attachment culture under the three-step induction protocol. Further, Notch signaling inhibition during pancreatic endoderm/progenitor induction yielded IPC colonies through the trend of glucose-responsive C-peptide secretion. Thus, this study showed that IPCs could be obtained from cBM-MSCs and cAD-MSCs through different induction techniques. Also, further signaling manipulation studies should be conducted to maximize the protocol’s efficiency.
Detection of significantly high vitreous concentrations of fatty acid-binding protein 4 in patients with proliferative diabetic retinopathy
Authors: Itoh Kaku , Furuhashi Masato , Ida Yosuke , Ohguro Hiroshi , Watanabe Megumi , Suzuki Soma , Hikage Fumihito
Published: June 2021

The fatty acid-binding protein4 (FABP4) and vascular endothelial growth factor A (VEGFA) play key roles in the metabolic and cardiovascular diseases, and proliferative diabetic retinopathy (PDR), respectively. To identify FABP4 in vitreous fluid in PDR, vitreous concentrations of FABP4 (V-FABP4) and VEGFA (V-VEGFA) from PDR (n = 20) and non-PDR (n = 20) patients were determined by Enzyme-Linked ImmunoSorbent Assays. The data, which included height and weight, systemic blood pressures, several blood biochemical parameters and blood flow at the optic nerve head (ONH) by laser speckle flowgraphy (LSFG) were collected. The levels of V-FABP4 and V-VEGFA were significantly higher in PDR patients than in non-PDR patients (P < 0.001) with a high positive correlation (r = 0.72, P < 0.001) between them. The findings were not affected by body mass index values and the presence of vitreous hemorrhaging. Among the clinical parameters, V-FABP4 correlated positively with creatinine and negatively with age and aspartate transaminase (AST) levels, while V-VEGFA correlated positively with fasting plasma glucose and hemoglobin A1c (HbA1c) levels but negatively with AST. Multiple regression analyses indicated that V-VEGFA, or V-FABP4, AST and HbA1c were independent predictors of V-FABP4 or V-VEGFA, respectively. Both were negatively correlated, but more evident in V-FABP4, with the ONH ocular blood flow.
In-vitro and in-vivo study of the interference between Rift Valley fever virus (clone 13) and Sheeppox/Lumpy Skin disease viruses
Authors: Safini N. , Bamouh Z. , Hamdi J. , Jazouli M. , Tadlaoui K. O. , El Harrak M.
Published: June 2021

Viral interference is a common occurrence that has been reported in cell culture in many cases. In the present study, viral interference between two capripox viruses (sheeppox SPPV and lumpy skin disease virus LSDV in cattle) with Rift Valley fever virus (RVFV) was investigated in vitro and in their natural hosts, sheep and cattle. A combination of SPPV/RVFV and LSDV/RVFV was used to co-infect susceptible cells and animals to detect potential competition. In-vitro interference was evaluated by estimating viral infectivity and copies of viral RNA by a qPCR during three serial passages in cell cultures, whereas in-vivo interference was assessed through antibody responses to vaccination. When lamb testis primary cells were infected with the mixture of capripox and RVFV, the replication of both SPPV and LSDV was inhibited by RVFV. In animals, SPPV/RVFV or LSDV/RVFV combinations inhibited the replication SPPV and LSDV and the antibody response following vaccination. The combined SPPV/RVFV did not protect sheep after challenging with the virulent strain of SPPV and the LSDV/RVFV did not induce interferon Gamma to LSDV, while immunological response to RVFV remain unaffected. Our goal was to assess this interference response to RVFV/capripoxviruses’ coinfection in order to develop effective combined live-attenuated vaccines as a control strategy for RVF and SPP/LSD diseases. Our findings indicated that this approach was not suitable for developing a combined SPPV/LSDV/RVFV vaccine candidate because of interference of replication and the immune response among these viruses.
Detailed head localization and incidence of skin cancers
Authors: Fijałkowska Marta , Koziej Mateusz , Antoszewski Bogusław
Published: June 2021

Skin cancers are the most common neoplasms; frequently, they localize on the face. The aim of paper is to present the incidence of skin tumors in a single center from 2017 to 2019, describe trends in its frequency and find relations between neoplasms and sex, type of cancer, and its size. An analysis of histopathological files from the surgical department between 2017 and 2019 was calculated. These items were selected: sex, age, type of skin cancer, subtype of basal cell carcinoma (BCC), grading of squamous cell carcinoma (SCC), localization and dimensions of the tumor. The study sample consisted of 387 cases. BCC was the most common cancer and its nodular type was the most frequent. In older patients, the vertical dimension of excised carcinoma was significantly larger. Moreover, this connection was detected only in women compared to men. There were statistically significant differences between dimensions of the skin cancer and sex. In men group, skin cancers had statistically higher vertical dimensions and larger surface areas. On the face and head, BCC more often localizes in the nasal area, while SCC on the auricle. It has been demonstrated that the older the patient, the larger the vertical dimension of the tumor. As such, tumor size is larger in men than in women, as women usually see their physicians sooner than men: cosmetic concerns are more important to them.
Serum gamma-glutamyl transferase, a marker of alcohol intake, is associated with telomere length and cardiometabolic risk in young adulthood
Authors: Bijnens Esmée M. , Derom Catherine , Thiery Evert , Martens Dries S. , Loos Ruth J. F. , Weyers Steven , Nawrot Tim S.
Published: June 2021

Studies based on self-reported alcohol consumption and telomere length show inconsistent results. Therefore, we studied the association between gamma-glutamyl transferase (GGT), a widely used biomarker of alcohol intake, and telomere length. The possible health relevance in young adulthood was explored by investigating cardiometabolic risk factors. Mixed modelling was performed to examine GGT and alcohol consumption in association with telomere length in buccal cells of 211 adults between 18 and 30 years old of the East Flanders Prospective Twin Survey. In addition, we investigated the association between GGT and cardiometabolic risk factors; waist circumference, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides. Although we did not observe an association between self-reported alcohol consumption and telomere length, our results show that a doubling in serum GGT is associated with 7.80% (95% CI − 13.9 to − 1.2%; p = 0.02) shorter buccal telomeres, independently from sex, chronological age, educational level, zygosity and chorionicity, waist-to-hip ratio and smoking. The association between GGT was significant for all five cardiometabolic risk factors, while adjusting for age. We show that GGT, a widely used biomarker of alcohol consumption, is associated with telomere length and with risk factors of cardiometabolic syndrome, despite the young age of this study population.
Micellar enhanced photo-induced fluorescence and absorbance for the development of an on-site early warning water quality monitoring system for pesticides
Authors: Bakhoum Jean-Pierre , Diop Ndeye A. , Bodian El Hadji T. , Mbaye Olivier M. A. , Diaw Pape. A. , Cisse Lamine , Gaye-Seye Mame D. , Thiare Diene D. , Coly Atanasse , Le Jeune Bernard , Giamarchi Philippe
Published: June 2021

This paper describes two prototypes of an on-site Early Warning Water Quality Monitoring System (EWWQMS) for pesticide quantification in natural waters.
An ultrasensitive electrochemical sensor for the detection of acetaminophenviaa three-dimensional hierarchical nanoporous gold wire electrode
Authors: Qian Lanting , Elmahdy Reem , Raj Thiruppathi Antony , Chen Aicheng
Published: June 2021

The study involves the unique fabrication of nanoporous gold with hierarchical pore sizes for the ultrasensitive detection of acetaminophen in sheep serum and lake water.
Harnessing lipid nanoparticles for efficient CRISPR delivery
Authors: Yan Jingyue , Kang Diana D. , Dong Yizhou
Published: June 2021

Lipid-based nanomaterials have shown to mediate specific and effective CRISPR delivery in vivo for the treatment of various diseases, including cancers, genetic disorders and infectious diseases.
Understanding water slippage through carbon nanotubes
Authors: Ma Cong , Chen Yun , Sun Guo En , Li Quan Ming , Gao Wang , Jiang Qing
Published: June 2021

The predominant role of hydrogen bonds in the continuum–subcontinuum transition for water slippage in carbon nanotubes.
Dysprosium(iii) compounds assembled via a versatile ligand incorporating salicylic hydrazide and 8-hydroxyquinolin units: syntheses, structures and magnetic properties
Authors: Zhang Li , Montigaud Vincent , Le Guennic Boris , Zhang Peng , Tang Jinkui
Published: June 2021

Assembly of dysprosium(iii) salts with versatile hydrazone H3L affords a variety of molecular magnetic compounds from mononuclear, dinuclear, grid-like tetranuclear to linear 1D chain.
Dissolution-based uptake of CeO2nanoparticles by freshwater shrimp – a dual-radiolabelling study of the fate of anthropogenic cerium in water organisms
Authors: Schymura Stefan , Rybkin Iaroslav , Uygan Seniha Simale Su , Drev Sandra , Podlipec Rok , Rijavec Tomaz , Mansel Alexander , Lapanje Ales , Franke Karsten , Strok Marko
Published: June 2021

A dual radiolabelling strategy was used to track CeO2NPs in freshwater shrimp showing a dissolution-based uptake pathway of cerium.
A novel Fe recycling method from pickling wastewater producing a KFeS2 whisker for electroplating wastewater treatment
Authors: Liang Dongxu , Ji Manhong , Zhu Suiyi , Chen Yu , Wang Zhihua , Liu Yanwen , Khan Asghar , Ri Kyonghun , Yu Hongbin , Huo Mingxin
Published: June 2021

Pickling sludge was converted to a novel product of KFeS2 nanorods via a facile hydrothermal method that effectively removes heavy metals from electroplating wastewater.
A simple and benign protocol for the synthesis of a deep eutectic solvent-based hydrophilic molecularly imprinted resin in water for excellent selective molecular recognition in aqueous phase
Authors: Wang Mingwei , Qiao Fengxia , Yan Hongyuan
Published: June 2021

A new deep eutectic solvent-based hydrophilic molecularly imprinted resin with excellent molecular recognition in aqueous phase was developed for the first time via a simple, efficient and green protocol.
Review on lignin modifications toward natural UV protection ingredient for lignin-based sunscreens
Authors: Tran My Ha , Phan Dieu-Phuong , Lee Eun Yeol
Published: June 2021

Lignin is a natural UV-blocking material owing to its aromatic structure with numerous phenolic, ketone, and intramolecular hydrogen bonds. To produce high-performance and applicable sunscreen from lignin, various modification methods can be applied.
Enhanced electrostatic potential with high energy and power density of a symmetric and asymmetric solid-state supercapacitor of boron and nitrogen co-doped reduced graphene nanosheets for energy storage devices
Authors: Pandian P. Muthu , Pandurangan A.
Published: June 2021

Schematic representation of boron and nitrogen co-doped graphene nanosheets.
The development of a highly selective fluorescent probe for the rapid detection of HClO in living cells and zebrafish
Authors: Liang Xing , Huo Yonghui , Yan Jun , Huang Ling , Lin Weiying
Published: June 2021

A new turn-on fluorescent probe, BM-HA, for the rapid detection of HClO in living cells and zebrafish is proposed, and DFT/TDDFT calculations provide insights into the optical properties of the BM-HA probe.
Tantalum(v) peroxido complexes as phosphatase inhibitors: a comparative studyvis-a-visperoxidovanadates
Authors: Saikia Gangutri , Talukdar Hiya , Ahmed Kabirun , Gour Nand Kishore , Islam Nashreen S.
Published: June 2021

Peroxido Ta(v) complexes are found to be more effective as inhibitors of wheat thylakoid acid phosphatasevis-à-vistheir V containing analogues. In addition, these compounds showed unique resistance towards degradation in the presence of catalase.
High molecular weight polyethylenimine encapsulated into a porous polymer monolithic by one-step polymerization for CO2 capture
Authors: Wang Shuoyu , Wu Jingjie , Ma Nianfang , Chen Shuixia
Published: June 2021

A low-cost porous polymer monolithic with a well-interconnected 3D structure and high amino efficiency for CO2 capture.
Crystallization of highly soluble thioglucopyranoside ejected by coherent molecular vibrational excitation using a visible 10 fs pulsed laser
Authors: Iwakura Izumi , Hashimoto Sena , Okamura Kotaro , Komori-Orisaku Keiko , Akai Shoji , Yabushita Atsushi
Published: June 2021

Under irradiation with a visible 10 fs pulsed laser, crystals can be formed by ejection from the solution phase to the gas phase due to coherent molecular vibrational excitation.
A benevolent direction to environmental suitability: ionic liquid immobilized MoO3 nanoparticles used in the efficient visible light-driven photocatalytic degradation of antibiotics
Authors: Chakraborty Debarati , Devi Meghali , Das Bishal , Barbhuiya Monjur H. , Dhar Siddhartha S. , Chowdhury Avijit
Published: June 2021

This paper summarizes the synthesis of a novel MoO3-bonded imidazolium sulfonic acid chloride (MoO3-IL) using a facile precipitation method and its application in the degradation of two organic pollutants.
Novel water-dispersible silicon nanoparticles as a fluorescent and colorimetric dual-mode probe for emodin detection
Authors: Pan Congjie , Wen Qiaoqiao , Ma Longfei , Qin Xuezhen , Feng Suxiang
Published: June 2021

A novel fluorescent and colorimetric dual-mode sensing method based on water-dispersible SiNPs was constructed for the sensitive detection of emodin.
Three-step method with self-sacrificial Co to prepare a uniform 5 nm-scale Pt catalyst for the oxygen reduction reaction
Authors: Li Donggang , Gong Yanlong , Li Gen , Lyu Xiao , Dai Zhenqing , Wang Qiang
Published: June 2021

Simple and rapid preparation method for a highly dispersed and small-sized CoPt catalyst.
Donor/acceptor substituted dithiafulvenes and tetrathiafulvalene vinylogues: electronic absorption, crystallographic, and computational analyses
Authors: Afzali Azadeh , Abdollahi Maryam F. , Zhang Baiyu , Zhao Yuming
Published: June 2021

The structural, electronic, and crystallographic properties of nitrophenyl and methoxyphenyl-substituted dithiafulvenes and tetrathiafulvalene vinylogues were systematically investigated by experimental and computational approaches.
Azido-perylenediimide: a versatile building block for CuAAC reactions and an alternative precursor for N-annulation
Authors: Goujon Antoine , Rocard Lou , Melnychenko Heorhii , Hudhomme Piétrick
Published: June 2021

Azido-perylenediimide readily transforms into N-annulated derivatives when exposed to light, and can be clicked in the dark.