bluuebunny/crossref_metadata_2025 huggingface dataset:
p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway
Authors: Guo Yitian , Rall-Scharpf Melanie , Bourdon Jean-Christophe , Wiesmüller Lisa , Biber Stephanie
Published: October 2021

The recently discovered p53-dependent DNA damage tolerance (DDT) pathway relies on its biochemical activities in DNA-binding, oligomerization, as well as complex formation with the translesion synthesis (TLS) polymerase iota (POLι). These p53-POLι complexes slow down nascent DNA synthesis for safe, homology-directed bypass of DNA replication barriers. In this study, we demonstrate that the alternative p53-isoforms p53β, p53γ, Δ40p53α, Δ133p53α, and Δ160p53α differentially affect this p53-POLι-dependent DDT pathway originally described for canonical p53α. We show that the C-terminal isoforms p53β and p53γ, comprising a truncated oligomerization domain (OD), bind PCNA. Conversely, N-terminally truncated isoforms have a reduced capacity to engage in this interaction. Regardless of the specific loss of biochemical activities required for this DDT pathway, all alternative isoforms were impaired in promoting POLι recruitment to PCNA in the chromatin and in decelerating DNA replication under conditions of enforced replication stress after Mitomycin C (MMC) treatment. Consistent with this, all alternative p53-isoforms no longer stimulated recombination, i.e., bypass of endogenous replication barriers. Different from the other isoforms, Δ133p53α and Δ160p53α caused a severe DNA replication problem, namely fork stalling even in untreated cells. Co-expression of each alternative p53-isoform together with p53α exacerbated the DDT pathway defects, unveiling impaired POLι recruitment and replication deceleration already under unperturbed conditions. Such an inhibitory effect on p53α was particularly pronounced in cells co-expressing Δ133p53α or Δ160p53α. Notably, this effect became evident after the expression of the isoforms in tumor cells, as well as after the knockdown of endogenous isoforms in human hematopoietic stem and progenitor cells. In summary, mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p53α functions in the p53-POLι-dependent DDT pathway.
Advancements in cathode catalyst and cathode layer design for proton exchange membrane fuel cells
Authors: Sun Yanyan , Polani Shlomi , Luo Fang , Ott Sebastian , Strasser Peter , Dionigi Fabio
Published: October 2021

Proton exchange membrane fuel cells have been recently developed at an increasing pace as clean energy conversion devices for stationary and transport sector applications. High platinum cathode loadings contribute significantly to costs. This is why improved catalyst and support materials as well as catalyst layer design are critically needed. Recent advances in nanotechnologies and material sciences have led to the discoveries of several highly promising families of materials. These include platinum-based alloys with shape-selected nanostructures, platinum-group-metal-free catalysts such as metal-nitrogen-doped carbon materials and modification of the carbon support to control surface properties and ionomer/catalyst interactions. Furthermore, the development of advanced characterization techniques allows a deeper understanding of the catalyst evolution under different conditions. This review focuses on all these recent developments and it closes with a discussion of future research directions in the field.
Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs
Authors: Sun Yu H. , Wang Ruoqiao Huiyi , Du Khai , Zhu Jiang , Zheng Jihong , Xie Li Huitong , Pereira Amanda A. , Zhang Chao , Ricci Emiliano P. , Li Xin Zhiguo
Published: October 2021

PIWI-interacting small RNAs (piRNAs) protect the germline genome and are essential for fertility. piRNAs originate from transposable element (TE) RNAs, long non-coding RNAs, or 3´ untranslated regions (3´UTRs) of protein-coding messenger genes, with the last being the least characterized of the three piRNA classes. Here, we demonstrate that the precursors of 3´UTR piRNAs are full-length mRNAs and that post-termination 80S ribosomes guide piRNA production on 3´UTRs in mice and chickens. At the pachytene stage, when other co-translational RNA surveillance pathways are sequestered, piRNA biogenesis degrades mRNAs right after pioneer rounds of translation and fine-tunes protein production from mRNAs. Although 3´UTR piRNA precursor mRNAs code for distinct proteins in mice and chickens, they all harbor embedded TEs and produce piRNAs that cleave TEs. Altogether, we discover a function of the piRNA pathway in fine-tuning protein production and reveal a conserved piRNA biogenesis mechanism that recognizes translating RNAs in amniotes.
Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression
Authors: Johann Kerstin , Bohn Toszka , Shahneh Fatemeh , Luther Natascha , Birke Alexander , Jaurich Henriette , Helm Mark , Klein Matthias , Raker Verena K. , Bopp Tobias , Barz Matthias , Becker Christian
Published: October 2021

The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
Shear relaxation governs fusion dynamics of biomolecular condensates
Authors: Ghosh Archishman , Kota Divya , Zhou Huan-Xiang
Published: October 2021

Phase-separated biomolecular condensates must respond agilely to biochemical and environmental cues in performing their wide-ranging cellular functions, but our understanding of condensate dynamics is lagging. Ample evidence now indicates biomolecular condensates as viscoelastic fluids, where shear stress relaxes at a finite rate, not instantaneously as in viscous liquids. Yet the fusion dynamics of condensate droplets has only been modeled based on viscous liquids, with fusion time given by the viscocapillary ratio (viscosity over interfacial tension). Here we used optically trapped polystyrene beads to measure the viscous and elastic moduli and the interfacial tensions of four types of droplets. Our results challenge the viscocapillary model, and reveal that the relaxation of shear stress governs fusion dynamics. These findings likely have implications for other dynamic processes such as multiphase organization, assembly and disassembly, and aging.
A self-healing catalyst for electrocatalytic and photoelectrochemical oxygen evolution in highly alkaline conditions
Authors: Feng Chao , Wang Faze , Liu Zhi , Nakabayashi Mamiko , Xiao Yequan , Zeng Qiugui , Fu Jie , Wu Qianbao , Cui Chunhua , Han Yifan , Shibata Naoya , Domen Kazunari , Sharp Ian D. , Li Yanbo
Published: October 2021

While self-healing is considered a promising strategy to achieve long-term stability for oxygen evolution reaction (OER) catalysts, this strategy remains a challenge for OER catalysts working in highly alkaline conditions. The self-healing of the OER-active nickel iron layered double hydroxides (NiFe-LDH) has not been successful due to irreversible leaching of Fe catalytic centers. Here, we investigate the introduction of cobalt (Co) into the NiFe-LDH as a promoter for in situ Fe redeposition. An active borate-intercalated NiCoFe-LDH catalyst is synthesized using electrodeposition and shows no degradation after OER tests at 10 mA cm−2 at pH 14 for 1000 h, demonstrating its self-healing ability under harsh OER conditions. Importantly, the presence of both ferrous ions and borate ions in the electrolyte is found to be crucial to the catalyst’s self-healing. Furthermore, the implementation of this catalyst in photoelectrochemical devices is demonstrated with an integrated silicon photoanode. The self-healing mechanism leads to a self-limiting catalyst thickness, which is ideal for integration with photoelectrodes since redeposition is not accompanied by increased parasitic light absorption.
RNA-seq of peripheral blood mononuclear cells of congenital generalized lipodystrophy type 2 patients
Authors: Huang Yen-Hua , Su Tzu-Chien , Wang Chung-Hsing , Wong Siew-Lee , Chien Yin-Hsiu , Wang Yu-Tai , Hwu Wuh-Liang , Lee Ni-Chung
Published: October 2021

Illumina RNA-seq analysis was used to characterize the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with congenital generalized lipodystrophy. RNA-seq information for seven patients with type 2 congenital generalized lipodystrophy (CGL2; Berardinelli-Seip congenital lipodystrophy, BSCL2) was obtained and compared with similar information for seven age- and sex-matched healthy control subjects. All seven CGL2 patients carried biallelic pathogenic mutations affecting the BSCL2 gene and had clinical symptoms of varying severity. The findings provide the whole-transcriptome signatures of PBMCs of CGL2 patients, allowing further exploration of gene expression patterns/signatures associated with the various clinical symptoms of patients with this disease.
Chagas disease and SARS-CoV-2 coinfection does not lead to worse in-hospital outcomes
Authors: Molina Israel , Marcolino Milena Soriano , Pires Magda Carvalho , Ramos Lucas Emanuel Ferreira , Silva Rafael Tavares , Guimarães-Júnior Milton Henriques , de Oliveira Isaias José Ramos , de Carvalho Rafael Lima Rodrigues , Nunes Aline Gabrielle Sousa , de Barros Ana Lara Rodrigues Monteiro , Scotton Ana Luiza Bahia Alves , Madureira Angélica Aparecida Coelho , Farace Bárbara Lopes , de Carvalho Cíntia Alcantara , Rodrigues Fernanda d’Athayde , Anschau Fernando , Botoni Fernando Antonio , Nascimento Guilherme Fagundes , Duani Helena , Guimarães Henrique Cerqueira , de Alvarenga Joice Coutinho , Moreira Leila Beltrami , Zandoná Liege Barella , de Almeida Luana Fonseca , Oliveira Luana Martins , Kopittke Luciane , de Castro Luís César , Santos Luisa Elem Almeida , de Souza Cabral Máderson Alvares , Ferreira Maria Angélica Pires , da Cunha Severino Sampaio Natália , de Oliveira Neimy Ramos , Assaf Pedro Ledic , Lopes Sofia Jarjour Tavares Starling , Fereguetti Tatiani Oliveira , dos Santos Veridiana Baldon , de Carvalho Victor Eliel Bastos , Ramires Yuri Carlotto , Ribeiro Antonio Luiz Pinho , Moscoso Freddy Antonio Brito , Moura Rogério , Polanczyk Carísi Anne , do Carmo Pereira Nunes Maria
Published: October 2021

Chagas disease (CD) continues to be a major public health burden in Latina America. Information on the interplay between COVID-19 and CD is lacking. Our aim was to assess clinical characteristics and in-hospital outcomes of patients with CD and COVID-19, and to compare it to non-CD patients. Consecutive patients with confirmed COVID-19 were included from March to September 2020. Genetic matching for sex, age, hypertension, diabetes mellitus and hospital was performed in a 4:1 ratio. Of the 7018 patients who had confirmed COVID-19, 31 patients with CD and 124 matched controls were included (median age 72 (64–80) years-old, 44.5% were male). At baseline, heart failure (25.8% vs. 9.7%) and atrial fibrillation (29.0% vs. 5.6%) were more frequent in CD patients than in the controls (p < 0.05). C-reactive protein levels were lower in CD patients compared with the controls (55.5 [35.7, 85.0] vs. 94.3 [50.7, 167.5] mg/dL). In-hospital management, outcomes and complications were similar between the groups. In this large Brazilian COVID-19 Registry, CD patients had a higher prevalence of atrial fibrillation and chronic heart failure compared with non-CD controls, with no differences in-hospital outcomes. The lower C-reactive protein levels in CD patients require further investigation.
Validation of algorithms for selecting rheumatoid arthritis patients in the Tuscan healthcare administrative databases
Authors: Convertino Irma , Cazzato Massimiliano , Giometto Sabrina , Gini Rosa , Valdiserra Giulia , Cappello Emiliano , Ferraro Sara , Tillati Silvia , Bartolini Claudia , Paoletti Olga , Lorenzoni Valentina , Trieste Leopoldo , Filippi Matteo , Turchetti Giuseppe , Cristofano Michele , Blandizzi Corrado , Mosca Marta , Lucenteforte Ersilia , Tuccori Marco
Published: October 2021

Validation of algorithms for selecting patients from healthcare administrative databases (HAD) is recommended. This PATHFINDER study section is aimed at testing algorithms to select rheumatoid arthritis (RA) patients from Tuscan HAD (THAD) and assessing RA diagnosis time interval between the medical chart date and that of THAD. A population was extracted from THAD. The information of the medical charts at the Rheumatology Unit of Pisa University Hospital represented the reference. We included first ever users of biologic disease modifying anti-rheumatic drugs (bDMARDs) between 2014 and 2016 (index date) with at least a specialist visit at the Rheumatology Unit of the Pisa University Hospital recorded from 2013 to the index date. Out of these, we tested four index tests (algorithms): (1) RA according to hospital discharge records or emergency department admissions (ICD-9 code, 714*); (2) RA according to exemption code from co-payment (006); (3) RA according to hospital discharge records or emergency department admissions AND RA according to exemption code from co-payment; (4) RA according to hospital discharge records or emergency department admissions OR RA according to exemption code from co-payment. We estimated sensitivity, specificity, positive and negative predicted values (PPV and NPV) with 95% confidence interval (95% CI) and the RA diagnosis median time interval (interquartile range, IQR). Two sensitivity analyses were performed. Among 277 reference patients, 103 had RA. The fourth algorithm identified 96 true RA patients, PPV 0.78 (95% CI 0.70–0.85), sensitivity 0.93 (95% CI 0.86–0.97), specificity 0.84 (95% CI 0.78–0.90), and NPV 0.95 (95% CI 0.91–0.98). The sensitivity analyses confirmed performance. The time measured between the actual RA diagnosis date recorded in medical charts and that assumed in THAD was 2.2 years (IQR 0.5–8.4). In conclusion, this validation showed the fourth algorithm as the best. The time interval elapsed between the actual RA diagnosis date in medical charts and that extrapolated from THAD has to be considered in the design of future studies.
Modulation of neural activity in frontopolar cortex drives reward-based motor learning
Authors: Herrojo Ruiz M. , Maudrich T. , Kalloch B. , Sammler D. , Kenville R. , Villringer A. , Sehm B. , Nikulin V. V.
Published: October 2021

The frontopolar cortex (FPC) contributes to tracking the reward of alternative choices during decision making, as well as their reliability. Whether this FPC function extends to reward gradients associated with continuous movements during motor learning remains unknown. We used anodal transcranial direct current stimulation (tDCS) over the right FPC to investigate its role in reward-based motor learning. Nineteen healthy human participants practiced novel sequences of finger movements on a digital piano with corresponding auditory feedback. Their aim was to use trialwise reward feedback to discover a hidden performance goal along a continuous dimension: timing. We additionally modulated the contralateral motor cortex (left M1) activity, and included a control sham stimulation. Right FPC-tDCS led to faster learning compared to lM1-tDCS and sham through regulation of motor variability. Bayesian computational modelling revealed that in all stimulation protocols, an increase in the trialwise expectation of reward was followed by greater exploitation, as shown previously. Yet, this association was weaker in lM1-tDCS suggesting a less efficient learning strategy. The effects of frontopolar stimulation were dissociated from those induced by lM1-tDCS and sham, as motor exploration was more sensitive to inferred changes in the reward tendency (volatility). The findings suggest that rFPC-tDCS increases the sensitivity of motor exploration to updates in reward volatility, accelerating reward-based motor learning.
Convergent cross sorting for estimating dynamic coupling
Authors: Breston Leo , Leonardis Eric J. , Quinn Laleh K. , Tolston Michael , Wiles Janet , Chiba Andrea A.
Published: October 2021

Natural systems exhibit diverse behavior generated by complex interactions between their constituent parts. To characterize these interactions, we introduce Convergent Cross Sorting (CCS), a novel algorithm based on convergent cross mapping (CCM) for estimating dynamic coupling from time series data. CCS extends CCM by using the relative ranking of distances within state-space reconstructions to improve the prior methods’ performance at identifying the existence, relative strength, and directionality of coupling across a wide range of signal and noise characteristics. In particular, relative to CCM, CCS has a large performance advantage when analyzing very short time series data and data from continuous dynamical systems with synchronous behavior. This advantage allows CCS to better uncover the temporal and directional relationships within systems that undergo frequent and short-lived switches in dynamics, such as neural systems. In this paper, we validate CCS on simulated data and demonstrate its applicability to electrophysiological recordings from interacting brain regions.
Study on the technology of enhancing permeability by deep hole presplitting blasting in Sanyuan coal mine
Authors: Zhao Dan , Wang Mingyu , Gao Xinhao
Published: October 2021

To reduce gas disasters in low permeability and high gas coal seams and improve gas predrainage efficiency, conventional deep hole presplitting blasting permeability increasing technology was refined and perfected. The damage degree of coal and rock blasting was quantitatively evaluated by using the value range of the damage variable D. According to the actual field test parameters of coal seam #3 in the Sanyuan coal mine, Dlim = 0.81 ~ 1.0 was the coal rock crushing area, Dlim = 0.19 ~ 0.81 was the coal rock crack area, and Dlim = 0 ~ 0.19 was the coal rock disturbance area. The blasting models under different blasting parameters were established by ANSYS/LS-DYNA software. The influence radius of single-hole blasting was 3.1 m, the hole diameter of double-hole blasting was 113 mm, the hole spacing was 5.5 m, and the delayed blasting time was 25 ms. According to the numerical simulation results, the determined parameters were tested on the working face of the 1312 transportation roadway in coal seam #3 of the Sanyuan coal mine. The results show that after blasting, the permeability of the original coal seam was increased by more than 30 times, the gas concentration was increased by 2.16 times, and the single hole purity and mixing volume were increased by 4.73 and 4.27 times, respectively. The positive effects of deep hole presplitting blasting permeability enhancement technology on the pressure relief and permeability enhancement of a low pressure and high gas coal seam were determined.
The expression, localisation and interactome of pigeon CRY2
Authors: Balay Spencer D. , Hochstoeger Tobias , Vilceanu Alexandra , Malkemper E. Pascal , Snider William , Dürnberger Gerhard , Mechtler Karl , Schuechner Stefan , Ogris Egon , Nordmann Gregory C. , Ushakova Lyubov , Nimpf Simon , Keays David A.
Published: October 2021

Cryptochromes (CRY) are highly conserved signalling molecules that regulate circadian rhythms and are candidate radical pair based magnetoreceptors. Birds have at least four cryptochromes (CRY1a, CRY1b, CRY2, and CRY4), but few studies have interrogated their function. Here we investigate the expression, localisation and interactome of clCRY2 in the pigeon retina. We report that clCRY2 has two distinct transcript variants,clCRY2a, and a previously unreported splice isoform,clCRY2bwhich is larger in size. We show thatclCRY2amRNA is expressed in all retinal layers andclCRY2bis enriched in the inner and outer nuclear layer. To define the localisation and interaction network of clCRY2 we generated and validated a monoclonal antibody that detects both clCRY2 isoforms. Immunohistochemical studies revealed that clCRY2a/b is present in all retinal layers and is enriched in the outer limiting membrane and outer plexiform layer. Proteomic analysis showed clCRY2a/b interacts with typical circadian molecules (PER2, CLOCK, ARTNL), cell junction proteins (CTNNA1, CTNNA2) and components associated with the microtubule motor dynein (DYNC1LI2, DCTN1, DCTN2, DCTN3) within the retina. Collectively these data show that clCRY2 is a component of the avian circadian clock and unexpectedly associates with the microtubule cytoskeleton.
Advice on comparing two independent samples of circular data in biology
Authors: Landler Lukas , Ruxton Graeme D. , Malkemper E. Pascal
Published: October 2021

Many biological variables are recorded on a circular scale and therefore need different statistical treatment. A common question that is asked of such circular data involves comparison between two groups: Are the populations from which the two samples are drawn differently distributed around the circle? We compared 18 tests for such situations (by simulation) in terms of both abilities to control Type-I error rate near the nominal value, and statistical power. We found that only eight tests offered good control of Type-I error in all our simulated situations. Of these eight, we were able to identify the Watson’s U2 test and a MANOVA approach, based on trigonometric functions of the data, as offering the best power in the overwhelming majority of our test circumstances. There was often little to choose between these tests in terms of power, and no situation where either of the remaining six tests offered substantially better power than either of these. Hence, we recommend the routine use of either Watson’s U2 test or MANOVA approach when comparing two samples of circular data.
Investigating the effects of polymer plugging mechanism of liquid production decrease and improvement by the cross-linked gel performance
Authors: Ma Kuiqian , Zene Mahamat Tahir Abdramane Mahamat , Baozhen Li , Jiang Ruizhong , Fan Haijun , Cui Yongzheng , Wei Liu Xiu
Published: October 2021

Polymer flooding, as the most successful and well-known chemical EOR method was broadly applied around the world. Mostly, contrasted with Waterflooding, the production rate decrease during polymer flooding is smaller based on field application. Nevertheless, the production liquid rate decreased critically in the middle phase to late phase due to plugging, which could lead the way to poor flooding performance and fewer cumulative oil. In this work, first, we approached the affecting polymer plugging mechanism model on liquid production decrease to investigate the parameters such as; solid-phase concentration (SOLIDMIN), reacting frequency factor (FREQFAC) and others affecting components are all investigated consecutively. Secondly the model approached by cross-linked gel for the improvement of production liquid rate. The physical work was designed by a physical model, and then the polymer adsorption that generating blockage emerging in permeability diminish assessed by a mathematical model. The outcomes specify that the existence of this debris, excessive assemblage of solid-phase and the excessive reactant frequency factor has major mechanical and physical parameters effects on the reservoir throughout polymer flooding. Polymer flood model base case liquid ratio loss is 11.15 m3/day between the years 2014-08-01 to 2020-03-04. Comparing with the polymer flood model case 1, liquid ratio loss ranging to 1.97 m3/day between the years 2014-08-02 to 2020-03-03. While the oil ratio loss of the polymer flood base case model between the years 2015-07-08 to 2020-03-04 attained 12.4 m3/day contrasting with the polymer flood model case 1 oil ratio increase to 0.37 m3/day between the years 2014-08-04 to 2019-04-02. The cross-linked gel model base case liquid ratio loss is 2.09 m3/day between the years 2015-01-02 to 2020-02-03, while the oil ratio lost reached 9.15 m3/day between the years 2015-09-01 to 2020-02-03. Contrasting with the cross-linked gel model case 2 liquid ratio recovered from the loss and attained 25.43 m3/day in the year 2020-12-01, while the oil ratio is reached 15.22 m3/day in the year 2020-12-01. Polymer flood model examined through cross-linked gel model performed reliable outcomes by taking out the plugging, which also occasioned the reservoir production rate to decrease. With the application of cross-linked gel the affected parameters and the production rate have achieved an improvement.
Low defect and high electrical conductivity of graphene through plasma graphene healing treatment monitored with in situ optical emission spectroscopy
Authors: Salehi Mohammad , Bastani Parnia , Jamilpanah Loghman , Madani Abbas , Mohseni Seyed Majid , Shokri Babak
Published: October 2021

Fundamental studies on graphene (Gr) and its real device applications have been affected by unavoidable defects and impurities which are usually present in synthesized Gr. Therefore, post treatment methods on Gr have been an important subject of research followed by the community. Here, we demonstrate a post-treatment of cm-sized CVD-grown graphene in a Radio Frequency-generated low-pressure plasma of methane and hydrogen to remove oxygen functional groups and heal the structural defects. The optimum plasma treatment parameters, such as pressure, plasma power, and the ratio of the gases, are optimized using in-situ optical emission spectroscopy. This way we present an optimal healing condition monitored with in situ OES. A twofold increase in the conductivity of plasma-treated Gr samples was obtained. Plasma treatment conditions give insights into the possible underlying mechanisms, and the method presents an effective way to obtain improved Gr quality.
Reliability and usefulness of the single leg heel raise balance test in patients with chronic ankle instability
Authors: Lee Jin Hyuck , Jung Hae Woon , Jung Taek Sung , Jang Woo Young
Published: October 2021

We aimed to analyze the differences in static (including conventional and modified [single-leg heel-raise balance]) and dynamic postural stability and muscle endurance between patients with chronic ankle instability (CAI) and healthy controls, and to determine the reliability and usefulness of the single-leg heel-raise balance test in patients with CAI. In total, 26 patients with CAI and 26 healthy controls were enrolled. Postural stability was assessed using a postural stabilometry system. Muscle endurance was measured in dorsiflexion and plantarflexion using an isokinetic device. Modified static postural stability (P < 0.001) and dynamic postural stability (P < 0.001) were significantly poorer in the affected ankles of patients with CAI than in the controls. Plantarflexion endurance was significantly lower in the affected ankles of the patients with CAI than in the controls (P = 0.023). Modified static postural stability significantly correlated with plantarflexion endurance in both groups (CAI group: r = − 0.470, P = 0.015; healthy controls group: r = − 0.413, P = 0.036). Plantarflexion endurance was a significant risk factor for modified static postural stability in both the CAI group (R2 = 0.221, P = 0.015) and healthy controls (R2 = 0.170, P = 0.036). Given the reliability of the modified static postural stability test, clinicians and therapists should consider using it to assess improvements in postural stability and muscle endurance in patients with CAI before and after rehabilitation.
Influence of dietary intervention on microvascular endothelial function in coronary patients and atherothrombotic risk of recurrence
Authors: Millan-Orge Marta , Torres-Peña Jose D. , Arenas-Larriva Antonio , Quintana-Navarro Gracia M. , Peña-Orihuela Patricia , Alcala-Diaz Juan F. , Luque Raul M. , Rodriguez-Cantalejo Fernando , Katsiki Niki , Lopez-Miranda Jose , Perez-Martinez Pablo , Delgado-Lista Javier
Published: October 2021

Endothelial dysfunction is a key player in both the onset and development of atherosclerosis. No study has examined whether healthy dietary patterns can improve microvascular endothelial function in patients with coronary heart disease (CHD) in the long-term and whether this relationship can affect patient’s risk of CHD recurrence. In the CORDIOPREV study, a randomized, double-blind, controlled trial, dietary intervention with either the Mediterranean diet or a low-fat diet was implemented in 1,002 CHD patients. A laser-doppler flowmetry was performed at baseline and after 6 years of follow up in 664 patients, evaluating the effects of this dietary intervention on microvascular basal flow and reactive hyperaemia area, as well as on the risk of CHD recurrence, based on the TRS2P risk score. Basal flow (97.78 ± 2.79 vs. 179.31 ± 5.06 arbitrary perfusion units, 83.38% increase, p < 0.001) and reactive hyperaemia area (4233.3 ± 127.73 vs. 9695.9 ± 205.23 arbitrary perfusion units per time, 129.04% increase, p < 0.001) improved after the dietary intervention in the cohort, without finding differences due to the diet (p > 0.05 for the diet-effect). When patients were stratified to low, moderate or high-risk of recurrence, basal flow was similarly increased in all three groups. However, reactive hyperaemia area was improved to a greater extent in patients at the low-risk group compared with those at moderate or high-risk. No differences were observed between diets. Healthy dietary patterns can improve microvascular endothelial function and this improvement persists in the long-term. Patients with a low-risk of CHD recurrence show a greater improvement in reactive vasodilation to ischemia than patients in the moderate or high-risk groups.
Ventricular longitudinal shortening is an independent predictor of death in heart failure patients with reduced ejection fraction
Authors: Berg J. , Jablonowski R. , Mohammad M. , Solem K. , Borgquist R. , Ostenfeld E. , Arheden H. , Carlsson M.
Published: October 2021

Reduced ventricular longitudinal shortening measured by atrioventricular plane displacement (AVPD) and global longitudinal strain (GLS) are prognostic markers in heart disease. This study aims to determine if AVPD and GLS with cardiovascular magnetic resonance (CMR) are independent predictors of cardiovascular (CV) and all-cause death also in heart failure with reduced ejection fraction (HFrEF). Patients (n = 287) were examined with CMR and AVPD, GLS, ventricular volumes, myocardial fibrosis/scar were measured. Follow-up was 5 years with cause of death retrieved from a national registry. Forty CV and 60 all-cause deaths occurred and CV non-survivors had a lower AVPD (6.4 ± 2.0 vs 8.0 ± 2.4 mm, p < 0.001) and worse GLS (− 6.1 ± 2.2 vs − 7.7 ± 3.1%, p = 0.001). Kaplan–Meier analyses displayed increased survival for patients in the highest AVPD- and GLS-tertiles vs. the lowest tertiles (AVPD: p = 0.001, GLS: p = 0.013). AVPD and GLS showed in univariate analysis a hazard ratio (HR) of 1.30 (per-mm-decrease) and 1.19 (per-%-decrease) for CV death. Mean AVPD and GLS were independent predictors of all-cause death (HR = 1.24 per-mm-decrease and 1.15 per-%-decrease), but only AVPD showed incremental value over age, sex, body-mass-index, EF, etiology and fibrosis/scar for CV death (HR = 1.33 per-mm-decrease, p < 0.001). Ventricular longitudinal shortening remains independently prognostic for death in HFrEF even after adjusting for well-known clinical risk factors.
Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets
Authors: Lavogina Darja , Laasfeld Tõnis , Vardja Markus , Lust Helen , Jaal Jana
Published: October 2021

Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.
Gene.iobio: an interactive web tool for versatile, clinically-driven variant interrogation and prioritization
Authors: Di Sera Tonya , Velinder Matt , Ward Alistair , Qiao Yi , Georges Stephanie , Miller Chase , Pitman Anders , Richards Will , Ekawade Aditya , Viskochil David , Carey John C. , Pace Laura , Bale Jim , Clardy Stacey L. , Andrews Ashley , Botto Lorenzo , Marth Gabor
Published: October 2021

With increasing utilization of comprehensive genomic data to guide clinical care, anticipated to become the standard of care in many clinical settings, the practice of diagnostic medicine is undergoing a notable shift. However, the move from single-gene or panel-based genetic testing to exome and genome sequencing has not been matched by the development of tools to enable diagnosticians to interpret increasingly complex or uncertain genomic findings. Here, we presentgene.iobio, a real-time, intuitive and interactive web application for clinically-driven variant interrogation and prioritization. We showgene.iobiois a novel and effective approach that significantly improves upon and reimagines existing methods. In a radical departure from existing methods that present variants and genomic data in text and table formats,gene.iobioprovides an interactive, intuitive and visually-driven analysis environment. We demonstrate that adoption ofgene.iobioin clinical and research settings empowers clinical care providers to interact directly with patient genomic data both for establishing clinical diagnoses and informing patient care, using sophisticated genomic analyses that previously were only accessible via complex command line tools.
Slower adaptation of control strategies in individuals with high impulsive tendencies
Authors: Grisetto Fanny , Delevoye-Turrell Yvonne N. , Roger Clémence
Published: October 2021

Flexible use of reactive and proactive control according to environmental demands is the key to adaptive behavior. In this study, forty-eight adults performed ten blocks of an AX-CPT task to reveal the strength of proactive control by the calculation of the proactive behavioral index (PBI). They also filled out the UPPS questionnaire to assess their impulsiveness. The median-split method based on the global UPPS score distribution was used to categorize participants as having high (HI) or low (LI) impulsiveness traits. The analyses revealed that the PBI was negatively correlated with the UPPS scores, suggesting that the higher is the impulsiveness, the weaker the dominance of proactive control processes. We showed, at an individual level, that the PBI increased across blocks and suggested that this effect was due to a smaller decrease in reactive control processes. Notably, the PBI increase was slower in the HI group than in the LI group. Moreover, participants who did not adapt to task demands were all characterized as high impulsive. Overall, the current study demonstrates that (1) impulsiveness is associated with less dominant proactive control due to (2) slower adaptation to task demands (3) driven by a stronger reliance on reactive processes. These findings are discussed in regards to pathological populations.
Quantitative evaluation of posture control in rats with inferior olive lesions
Authors: Funato Tetsuro , Sato Yota , Sato Yamato , Fujiki Soichiro , Aoi Shinya , Tsuchiya Kazuo , Yanagihara Dai
Published: October 2021

Impairment of inferior olivary neurons (IONs) affects whole-body movements and results in abnormal gait and posture. Because IONs are activated by unpredicted motion rather than regular body movements, the postural dysfunction caused by ION lesions is expected to involve factors other than simple loss of feedback control. In this study, we measured the postural movements of rats with pharmacological ION lesions (IO rats) trained to stand on their hindlimbs. The coordination of body segments as well as the distribution and frequency characteristics of center of mass (COM) motion were analyzed. We determined that the lesion altered the peak properties of the power spectrum density of the COM, whereas changes in coordination and COM distribution were minor. To investigate how the observed properties reflected changes in the control system, we constructed a mathematical model of the standing rats and quantitatively identified the control system. We found an increase in linear proportional control and a decrease in differential and nonlinear control in IO rats compared with intact rats. The dystonia-like changes in body stiffness explain the nature of the linear proportional and differential control, and a disorder in the internal model is one possible cause of the decrease in nonlinear control.
Genomic prediction for testes weight of the tiger pufferfish, Takifugu rubripes, using medium to low density SNPs
Authors: Hosoya Sho , Yoshikawa Sota , Sato Mana , Kikuchi Kiyoshi
Published: October 2021

Aquaculture production is expected to increase with the help of genomic selection (GS). The possibility of performing GS using only a small number of SNPs has been examined in order to reduce genotyping costs; however, the practicality of this approach is still unclear. Here, we tested whether the effects of reducing the number of SNPs impaired the prediction accuracy of GS for standard length, body weight, and testes weight in the tiger pufferfish (Takifugu rubripes). High values for predictive ability (0.563–0.606) were obtained with 4000 SNPs for all traits under a genomic best linear unbiased predictor (GBLUP) model. These values were still within an acceptable range with 1200 SNPs (0.554–0.588). However, predictive abilities and prediction accuracies deteriorated using less than 1200 SNPs largely due to the reduced power in accurately estimating the genetic relationship among individuals; family structure could still be resolved with as few as 400 SNPs. This suggests that the SNPs informative for estimation of genetic relatedness among individuals differ from those for inference of family structure, and that non-random SNP selection based on the effects on family structure (e.g., site-FST, principal components, or random forest) is unlikely to increase the prediction accuracy for these traits.
Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker
Authors: Poblocka Marta , Bassey Akang Leonard , Smith Victoria M. , Falcicchio Marta , Manso Ana Sousa , Althubiti Mohammad , Sheng XiaoBo , Kyle Andrew , Barber Ruth , Frigerio Mark , Macip Salvador
Published: October 2021

A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila
Authors: Giachello Carlo N. G. , Fan Yuen Ngan , Landgraf Matthias , Baines Richard A.
Published: October 2021

The emergence of coordinated network function during nervous system development is often associated with critical periods. These phases are sensitive to activity perturbations during, but not outside, of the critical period, that can lead to permanently altered network function for reasons that are not well understood. In particular, the mechanisms that transduce neuronal activity to regulating changes in neuronal physiology or structure are not known. Here, we take advantage of a recently identified invertebrate model for studying critical periods, the Drosophila larval locomotor system. Manipulation of neuronal activity during this critical period is sufficient to increase synaptic excitation and to permanently leave the locomotor network prone to induced seizures. Using genetics and pharmacological manipulations, we identify nitric oxide (NO)-signaling as a key mediator of activity. Transiently increasing or decreasing NO-signaling during the critical period mimics the effects of activity manipulations, causing the same lasting changes in synaptic transmission and susceptibility to seizure induction. Moreover, the effects of increased activity on the developing network are suppressed by concomitant reduction in NO-signaling and enhanced by additional NO-signaling. These data identify NO signaling as a downstream effector, providing new mechanistic insight into how activity during a critical period tunes a developing network.
Mask wearing increases eye involvement during smiling: a facial EMG study
Authors: Okazaki Shuntaro , Yamanami Haruna , Nakagawa Fumika , Takuwa Nozomi , Kawabata Duncan Keith James
Published: October 2021

The use of face masks has become ubiquitous. Although mask wearing is a convenient way to reduce the spread of disease, it is important to know how the mask affects our communication via facial expression. For example, when we are wearing the mask and meet a friend, are our facial expressions different compared to when we are not? We investigated the effect of face mask wearing on facial expression, including the area around the eyes. We measured surface electromyography from zygomaticus major, orbicularis oculi, and depressor anguli oris muscles, when people smiled and talked with or without a mask. Only the actions of the orbicularis oculi were facilitated by wearing the mask. We thus concluded that mask wearing may increase the recruitment of the eyes during smiling. In other words, we can express joy and happiness even when wearing a face mask.
Ten years of pluviometric analyses in Italy for civil protection purposes
Authors: Del Soldato Matteo , Rosi Ascanio , Delli Passeri Luca , Cacciamani Carlo , Catani Filippo , Casagli Nicola
Published: October 2021

The concept of climate change has grown in recent decades, influencing the scientific community to conduct research on meteorological parameters and their variabilities. Research on global warming, as well as on its possible economic and environmental consequences, has spread over the last 20 years. Diffused changes in trends have been stated by several authors throughout the world, with different developments observed depending on the continent. Following a period of approximately 40 days of almost continuous rain that occurred from October to November 2019 across the Italian territory and caused several hazards (e.g., floods and landslides), a relevant question for decision-makers and civil protection actors emerged regarding the relative frequencies of given rainfall events in the Warning Hazard Zones (WHZs) of Italy. The derived products of this work could answer this question for both weather and hydrogeological operators thanks to the frequency and spatio-temporal distribution analyses conducted on 10-year daily rainfall data over the entire Italian territory. This work aspires to be an additional tool used to analyse events that have occurred, providing further information for a better understanding of the probability of occurrence and distribution of future events.
Organocatalytic atroposelective heterocycloaddition to access axially chiral 2-arylquinolines
Authors: Yang Gongming , Sun Shaofa , Li Zhipeng , Liu Yuhan , Wang Jian
Published: October 2021

Axially chiral heterobiaryls play a vital role in asymmetric synthesis and drug discovery. However, there are few reports on the synthesis of atropisomeric heterobiaryls compared with axially chiral biaryls. Thus, the rapid enantioselective construction of optically active heterobiaryls and their analogues remains an attractive challenge. Here, we report a concise chiral amine-catalyzed atroposelective heterocycloaddition reaction of alkynes with ortho-aminoarylaldehydes, and obtain a new class of axially chiral 2-arylquinoline skeletons with high yields and excellent enantioselectivities. In addition, the axially chiral 2-arylquinoline framework with different substituents is expected to be widely used in enantioselective synthesis.