bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of physical activity intervention and nutritional habits on anthropometric measures in elementary school children: the health oriented pedagogical project (HOPP)
Authors: Goswami Nandu , Trozic Irhad , Fredriksen Maren Valand , Fredriksen Per Morten
Published: May 2021

Background

Overweight and obesity are a burden of the modern world that requires urgent action. Prevention has proven to be efficient in the fight against overweight and obesity. As many children gain excessive weight at an early age, intervention during school years are important. While daily physical activity (PA) is known to have an influence on overweight and obesity prevention, the importance of a healthy lifestyle, including dietary habits, should not be underestimated. The aim of this study was to assess how a combination of daily PA and healthy/unhealthy diet affect the anthropometric measures of 4th graders in Norway.

Methods

The Health Oriented Pedagogical Project (HOPP) is a longitudinal intervention in primary school children, which includes increased amount of daily physical activity during teaching– active learning. Assessed were weight, muscle and bone mass, as well as fat mass, using a bio-impedance Tanita scale. A dietary survey, Ungkost 2000, with 18 multiple-choice questions was used to evaluate the overall nutrition characteristics of the children.

Results

Between 2015 and 2018, a total of 917 (intervention group n = 614, control group n = 303) 4th graders from nine different schools from the south–east part of Norway participated. We observed that daily PA and a regular healthy diet increases—while an unhealthy diet decreases—muscle and bone mass despite daily PA. Daily PA appears to counteract some of the effects of an unhealthy diet on weight and fat mass. In addition, daily PA and a regular intake of fruits and berries lowers weight and fat mass in children with overweight.

Conclusion

Combination of daily 45-minute of PA and a healthy diet leads to reductions in body weight and incease in muscle and bone mass in elementary school children.
Gene expression derived from alternative promoters improves prognostic stratification in multiple myeloma
Authors: Valcárcel Luis V. , Amundarain Ane , Kulis Marta , Charalampopoulou Stella , Melnick Ari , San Miguel Jesús , Martín-Subero José I. , Planes Francisco J. , Agirre Xabier , Prosper Felipe
Published: May 2021

Clinical and genetic risk factors are currently used in multiple myeloma (MM) to stratify patients and to design specific therapies. However, these systems do not capture the heterogeneity of the disease supporting the development of new prognostic factors. In this study, we identified active promoters and alternative active promoters in 6 different B cell subpopulations, including bone-marrow plasma cells, and 32 MM patient samples, using RNA-seq data. We find that expression initiated at both regular and alternative promoters was specific of each B cell subpopulation or MM plasma cells, showing a remarkable level of consistency with chromatin-based promoter definition. Interestingly, using 595 MM patient samples from the CoMMpass dataset, we observed that the expression derived from some alternative promoters was associated with lower progression-free and overall survival in MM patients independently of genetic alterations. Altogether, our results define cancer-specific alternative active promoters as new transcriptomic features that can provide a new avenue for prognostic stratification possibilities in patients with MM.
Viral dynamics and antibody responses in people with asymptomatic SARS-CoV-2 infection
Authors: Sui Zhiwei , Dai Xinhua , Lu Qingbin , Zhang Yulan , Huang Min , Li Shufen , Peng Tao , Xie Jie , Zhang Yongzhuo , Wu Chunchen , Xia Jianbo , Dong Lianhua , Yang Jiayi , Huang Wenfeng , Liu Siyuan , Wang Ziquan , Li Ke , Yang Qingfang , Zhou Xi , Wu Ying , Liu Wei , Fang Xiang , Peng Ke
Published: May 2021

Over 40% of the coronavirus disease 2019 (COVID-19) COVID-19 patients were asymptomatically infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the immune responses of these asymptomatic individuals is a critical factor for developing the strategy to contain the COVID-19 pandemic. Here, we determined the viral dynamics and antibody responses among 143 asymptomatic individuals identified in a massive screening of more than 5 million people in eight districts of Wuhan in May 2020. Asymptomatic individuals were admitted to the government-designated centralized sites in accordance with policy. The incidence rate of asymptomatic infection is ~2.92/100,000. These individuals had low viral copy numbers (peaked at 315 copies/mL) and short-lived antibody responses with the estimated diminish time of 69 days. The antibody responses in individuals with persistent SARS-CoV-2 infection is much longer with the estimated diminish time of 257 days. These results imply that the immune responses in the asymptomatic individuals are not potent enough for preventing SARS-CoV-2 re-infection, which has recently been reported in recovered COVID-19 patients. This casts doubt on the efficacy of forming “herd-immunity” through natural SARS-CoV-2 infection and urges for the development of safe and effective vaccines.
Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer
Authors: Ring Alistair , Battisti Nicolò Matteo Luca , Reed Malcolm W. R. , Herbert Esther , Morgan Jenna L. , Bradburn Michael , Walters Stephen J. , Collins Karen A. , Ward Sue E. , Holmes Geoffrey R. , Burton Maria , Lifford Kate , Edwards Adrian , Robinson Thompson G. , Martin Charlene , Chater Tim , Pemberton Kirsty J. , Brennan Alan , Cheung Kwok Leung , Todd Annaliza , Audisio Riccardo A. , Wright Juliet , Simcock Richard , Green Tracey , Revell Deirdre , Gath Jacqui , Horgan Kieran , Holcombe Chris , Winter Matthew C. , Naik Jay , Parmeshwar Rishi , Gosney Margot A. , Hatton Matthew Q. , Thompson Alastair M. , Wyld Lynda ,   on behalf of the Age Gap TMG, Collins Karen , Ward Sue , Holmes Geoff , Morgan Jenna , Bradburn Mike , Walters Stephen , Burton Maria , Lifford Kate , Edwards Adrian , Brain Kate , Ring Alistair , Robinson Thomson , Pemberton Kirsty , Shrestha Anne , Nettleship Anthony , Richards Paul , Cheung Kwok Leung , Harder Helena , Audisio Riccardo , Battisti Nicolò Matteo Luca , Wright Juliette , Simcock Richard , Murray Chris , Thomson Alistair M. , Gosney Margot , Hatton Matthew , Armitage Fiona , Patnick Julietta , Green Tracy , Revill Deirdre , Gath Jacqui , Horgan Kieran , Holcombe Chris , Winter Matt
Published: May 2021

Background

Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy.

Methods

A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage.

Results

Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed.

Conclusions

Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient.

Trial Registration

ISRCTN 46099296
Human adipose tissue-derived mesenchymal stem cells and their extracellular vesicles modulate lipopolysaccharide activated human microglia
Authors: Garcia-Contreras Marta , Thakor Avnesh S.
Published: May 2021

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), are driven by neuroinflammation triggered by activated microglial cells; hence, the phenotypic regulation of these cells is an appealing target for intervention. Human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) may be a potential therapeutic candidate to treat NDs given their immunomodulatory properties. Evidence suggests that the mechanism of action of hAD-MSCs is through their secretome, which includes secreted factors such as cytokines, chemokines, or growth factors as well as extracellular vesicles (EVs). Recently, EVs have emerged as important mediators in cell communication given, they can transfer proteins, lipids, and RNA species (i.e., miRNA, mRNA, and tRNAs) to modulate recipient cells. However, the therapeutic potential of hAD-MSCs and their secreted EVs has not been fully elucidated with respect to human microglia. In this study, we determined the therapeutic potential of different hAD-MSCs doses (200,000, 100,000, and 50,000 cells) or their secreted EVs (50, 20, or 10 µg/ml), on human microglial cells (HMC3) that were activated by lipopolysaccharides (LPS). Upregulation of inducible nitric oxide synthase (iNOS), an activation marker of HMC3 cells, was prevented when they were cocultured with hAD-MSCs and EVs. Moreover, hAD-MSCs inhibited the secretion of proinflammatory factors, such as IL-6, IL-8, and MCP-1, while their secreted EVs promoted the expression of anti-inflammatory mediators such as IL-10 or TIMP-1 in activated microglia. The present data therefore support a role for hAD-MSCs and their secreted EVs, as potential therapeutic candidates for the treatment of NDs.
ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets
Authors: Marsh Glenn A. , McAuley Alexander J. , Au Gough G. , Riddell Sarah , Layton Daniel , Singanallur Nagendrakumar B. , Layton Rachel , Payne Jean , Durr Peter A. , Bender Hannah , Barr Jennifer A. , Bingham John , Boyd Victoria , Brown Sheree , Bruce Matthew P. , Burkett Kathie , Eastwood Teresa , Edwards Sarah , Gough Tamara , Halpin Kim , Harper Jenni , Holmes Clare , Horman William S. J. , van Vuren Petrus Jansen , Lowther Suzanne , Maynard Kate , McAuley Kristen D. , Neave Matthew J. , Poole Timothy , Rootes Christina , Rowe Brenton , Soldani Elisha , Stevens Vittoria , Stewart Cameron R. , Suen Willy W. , Tachedjian Mary , Todd Shawn , Trinidad Lee , Walter Duane , Watson Naomi , Drew Trevor W. , Gilbert Sarah C. , Lambe Teresa , Vasan S. S.
Published: May 2021

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.
Thermal transport investigation in AA7072 and AA7075 aluminum alloys nanomaterials based radiative nanofluids by considering the multiple physical flow conditions
Authors: Adnan  , Ullah Khan Sheikh Irfan , Khan Umar , Ahmed Naveed , Mohyud-Din Syed Tauseef , Khan Ilyas , Nisar Kottakkaran Sooppy
Published: May 2021

Now a day’s variety of nanomaterials is available, among these Aluminum Alloys AA7072 and AA705 are significant due to their thermal, physical and mechanical characteristics. These extensively used in manufacturing of spacecraft, aircraft parts and building testing. Keeping in view the significance of nanoliquids, the analysis of methanol suspended by AA7072 and AA7075 alloys under the multiple physical flow conditions is reported. The model is successfully treated by coupling of RK and shooting algorithm and examined the results for the flow regimes by altering the ingrained physical parameters. Then physical interpretation of the results discussed comprehensively. To validate the analysis, a comparison between the presented and existing is reported under certain assumptions on the flow parameters. It is found that the results are reliable inline with existing once.
Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model
Authors: Saraiva Sofia M. , Gutiérrez-Lovera Carlha , Martínez-Val Jeannette , Lores Sainza , Bouzo Belén L. , Díez-Villares Sandra , Alijas Sandra , Pensado-López Alba , Vázquez-Ríos Abi Judit , Sánchez Laura , de la Fuente María
Published: May 2021

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.
Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
Authors: Hébert Audrey , Parisotto Maxime , Rowell Marie-Camille , Doré Alexandra , Fernandez Ruiz Ana , Lefrançois Guillaume , Kalegari Paloma , Ferbeyre Gerardo , Schmitzer Andreea R.
Published: May 2021

We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.
Mutations as Levy flights
Authors: Leon Dario A. , Gonzalez Augusto
Published: May 2021

Data from a long time evolution experiment with Escherichia Coli and from a large study on copy number variations in subjects with European ancestry are analyzed in order to argue that mutations can be described as Levy flights in the mutation space. These Levy flights have at least two components: random single-base substitutions and large DNA rearrangements. From the data, we get estimations for the time rates of both events and the size distribution function of large rearrangements.
Improvement of mechanical properties of HfB2-based composites by incorporating in situ SiC reinforcement through pressureless sintering
Authors: Ghadami S. , Taheri-Nassaj E. , Baharvandi H. R. , Ghadami F.
Published: May 2021

HfB2, Si, and activated carbon powders were selected to fabricate 0–30 vol% SiC reinforced HfB2-based composite. Pressureless sintering process was performed at 2050 °C for 4 h under a vacuum atmosphere. Microstructural studies revealed that in situ SiC reinforcement was formed and distributed in the composite according to the following reaction: Si + C = SiC. A maximum relative density of 98% was measured for the 20 vol% SiC containing HfB2 composite. Mechanical investigations showed that the hardness and the fracture toughness of these composites were increased and reached up to 21.2 GPa for HfB2-30 vol% SiC and 4.9 MPa.m1/2 for HfB2-20 vol% SiC, respectively. Results showed that alpha-SiC reinforcements were created jagged, irregular, and elongated in shape which were in situ formed between HfB2 grains and filled the porosities. Formation of alpha-SiC contributed to improving the relative density and mechanical properties of the composite samples. By increasing SiC content, an enhanced trend of thermal conductivity was observed as well as a reduced trend for electrical conductivity.
A randomized trial of safety and pharmacodynamic interactions between a selective glucocorticoid receptor antagonist, PT150, and ethanol in healthy volunteers
Authors: Morice Claire , Baker Dewleen G. , Patel Marguerite M. , Nolen Tracy L. , Nowak Kayla , Hirsch Shawn , Kosten Thomas R. , Verrico Christopher D.
Published: May 2021

PT150, a novel competitive glucocorticoid receptor (GR) antagonist, has proven safe in animal models, healthy volunteers, and people with depression. Our study is the first to investigate PT150’s safety with alcohol use. The primary objective of this study was to evaluate pharmacodynamic interactions between ethanol and PT150 in healthy subjects. This single-site, Phase I pilot trial consisted of community-recruited, healthy, alcohol-experienced participants aged 21–64 years. Of 32 participants screened, 11 were enrolled and randomized, one of which withdrew before intervention. PT150 (900 mg/day) was administered orally to all participants for five days. All participants received two beverage challenges on Day 1 (before PT150 administration) and Day 5 (after PT150 administration). On challenge days, they received both alcohol (16% ethanol) and placebo (1% ethanol) beverages in random order. Primary outcomes included breath alcohol level, blood pressure, heart rate, adverse events, and electrocardiogram changes. There were no statistically significant differences in vital signs or estimated blood alcohol concentrations between PT150 non-exposed and exposed groups during the ethanol challenge. There were no clinically significant abnormal electrocardiograms or serious adverse events. These data show that administration of PT150 with concurrent alcohol use is safe and well-tolerated. This study supports a future pharmacokinetic interaction study between PT150 and alcohol.

Trial Registration ClinicalTrials.gov Identifier: NCT03548714.
Numerical study of nano-biofilm stagnation flow from a nonlinear stretching/shrinking surface with variable nanofluid and bioconvection transport properties
Authors: Alsenafi Abdulaziz , Bég O. Anwar , Ferdows M. , Bég Tasveer A. , Kadir A.
Published: May 2021

A mathematical model is developed for stagnation point flow toward a stretching or shrinking sheet of liquid nano-biofilm containing spherical nano-particles and bioconvecting gyrotactic micro-organisms. Variable transport properties of the liquid (viscosity, thermal conductivity, nano-particle species diffusivity) and micro-organisms (species diffusivity) are considered. Buongiorno’s two-component nanoscale model is deployed and spherical nanoparticles in a dilute nanofluid considered. Using a similarity transformation, the nonlinear systems of partial differential equations is converted into nonlinear ordinary differential equations. These resulting equations are solved numerically using a central space finite difference method in the CodeBlocks Fortran platform. Graphical plots for the distribution of reduced skin friction coefficient, reduced Nusselt number, reduced Sherwood number and the reduced local density of the motile microorganisms as well as the velocity, temperature, nanoparticle volume fraction and the density of motile microorganisms are presented for the influence of wall velocity power-law index (m), viscosity parameter $$({c}_{2})$$

(

c
2

)

, thermal conductivity parameter (c4), nano-particle mass diffusivity (c6), micro-organism species diffusivity (c8), thermophoresis parameter $$(Nt)$$

(
N
t
)

, Brownian motion parameter $$(Nb)$$

(
N
b
)

, Lewis number $$(Le)$$

(
L
e
)

, bioconvection Schmidt number $$(Sc)$$

(
S
c
)

, bioconvection constant (σ) and bioconvection Péclet number $$(Pe)$$

(
P
e
)

. Validation of the solutions via comparison related to previous simpler models is included. Further verification of the general model is conducted with the Adomian decomposition method (ADM). Extensive interpretation of the physics is included. Skin friction is elevated with viscosity parameter ($${\mathrm{c}}_{2})$$

c
2

)

whereas it is suppressed with greater Lewis number and thermophoresis parameter. Temperatures are elevated with increasing thermal conductivity parameter ($${\mathrm{c}}_{4})$$

c
4

)

whereas Nusselt numbers are reduced. Nano-particle volume fraction (concentration) is enhanced with increasing nano-particle mass diffusivity parameter ($${c}_{6}$$

c
6

) whereas it is markedly reduced with greater Lewis number (Le) and Brownian motion parameter (Nb). With increasing stretching/shrinking velocity power-law exponent ($$m),$$

m
)
,

skin friction is decreased whereas Nusselt number and Sherwood number are both elevated. Motile microorganism density is boosted strongly with increasing micro-organism diffusivity parameter ($${\mathrm{c}}_{8}$$

c
8

) and Brownian motion parameter (Nb) but reduced considerably with greater bioconvection Schmidt number (Sc) and bioconvection Péclet number (Pe). The simulations find applications in deposition processes in nano-bio-coating manufacturing processes.
Light quality and quantity affect graft union formation of tomato plants
Authors: Yousef Ahmed Fathy , Ali Muhammad Moaaz , Rizwan Hafiz Muhammad , Gad Ahmed Gomaa , Liang Dangdi , Binqi Li , kalaji Hazem M. , Wróbel Jacek , Xu Yong , Chen Faxing
Published: May 2021

It is already known that there are many factors responsible for the successful formation of a graft union. However, the role of light has been little studied. In an anatomical study, Scanning Electronic Microscope (SEM) was used to explore the effects of different light-emitting diodes (LEDs) on graft union formation in grafted tomato. In addition, the expression genes related to Auxin hormone signaling pathway (SAUR67, AUX1, ARF30, and LAX3) was investigated. The obtained results showed that the concrescence process occurred faster under R7:B3 light conditions, as compared to blue (B) and white fluorescent (WFL) lights. Red light application caused a delay in the vascular tissue differentiation, which may lead to callus development on both sides, causing junctional failure and resulting in ineffective graft junctional arrangement. The expression of genes related to Auxin hormone significantly increased by R7:B3 application. We suggest that LED spectra affects the graft development of tomato plants and can improve the performance of grafted tomato seedlings.
Wide and increasing suitability for Aedes albopictus in Europe is congruent across distribution models
Authors: Oliveira Sandra , Rocha Jorge , Sousa Carla A. , Capinha César
Published: May 2021

The Asian tiger mosquito (Aedes albopictus), a vector of dengue, Zika and other diseases, was introduced in Europe in the 1970s, where it is still widening its range. Spurred by public health concerns, several studies have delivered predictions of the current and future distribution of the species for this region, often with differing results. We provide the first joint analysis of these predictions, to identify consensus hotspots of high and low suitability, as well as areas with high uncertainty. The analysis focused on current and future climate conditions and was carried out for the whole of Europe and for 65 major urban areas. High consensus on current suitability was found for the northwest of the Iberian Peninsula, southern France, Italy and the coastline between the western Balkans and Greece. Most models also agree on a substantial future expansion of suitable areas into northern and eastern Europe. About 83% of urban areas are expected to become suitable in the future, in contrast with ~ 49% nowadays. Our findings show that previous research is congruent in identifying wide suitable areas for Aedes albopictus across Europe and in the need to effectively account for climate change in managing and preventing its future spread.
New radiometric 40Ar–39Ar dates and faunistic analyses refine evolutionary dynamics of Neogene vertebrate assemblages in southern South America
Authors: Prevosti Francisco J. , Romano Cristo O. , Forasiepi Analía M. , Hemming Sidney , Bonini Ricardo , Candela Adriana M. , Cerdeño Esperanza , Madozzo Jaén M. Carolina , Ortiz Pablo E. , Pujos François , Rasia Luciano , Schmidt Gabriela I. , Taglioretti Matias , MacPhee Ross D. E. , Pardiñas Ulyses F. J.
Published: May 2021

The vertebrate fossil record of the Pampean Region of Argentina occupies an important place in South American vertebrate paleontology. An abundance of localities has long been the main basis for constructing the chronostratigraphical/geochronological scale for the late Neogene–Quaternary of South America, as well as for understanding major patterns of vertebrate evolution, including the Great American Biotic Interchange. However, few independently-derived dates are available for constraining this record. In this contribution, we present new40Ar/39Ar dates on escorias (likely the product of meteoric impacts) from the Argentinean Atlantic coast and statistically-based biochronological analyses that help to calibrate Late Miocene–Pliocene Pampean faunal successions. For the type areas of the Montehermosan and Chapadmalalan Ages/Stages, our results delimit their age ranges to 4.7–3.7 Ma and ca. 3.74–3.04 Ma, respectively. Additionally, from Buenos Aires Province, dates of 5.17 Ma and 4.33 Ma were recovered for “Huayquerian” and Montehermosan faunas. This information helps to better calibrate important first appearances of allochthonous taxa in South America, including one of the oldest records for procyonids (7.24–5.95 Ma), cricetids (6.95–5.46 Ma), and tayassuids (> 3.74 Ma, oldest high-confidence record). These results also constrain to ca. 3 Ma the last appearances of the autochthonous sparassodonts, as well as terror birds of large/middle body size in South America. South American faunal turnover during the late Neogene, including Late Pliocene extinctions, is interpreted as a consequence of knock-on effects from global climatic changes and initiation of the icehouse climate regime.
Determination of a microRNA signature of protective kidney ischemic preconditioning originating from proximal tubules
Authors: Khalid Usman , Jenkins Robert H. , Andrews Robert , Pino-Chavez Gilda , Cossins Benjamin C. , Chavez Rafael , Bowen Timothy , Fraser Donald J.
Published: May 2021

Ischemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia–reperfusion injury (IRI). We found optimal protection from subsequent injury following short, repetitive sequences of preconditioning insult. We subsequently used hybridization array and microRNA sequencing to characterize microRNA signatures of protective IPC and of IRI. These approaches identified a profile of microRNA changes consequent on IRI, that were limited by prior IPC. To localize these signals within the kidney, we used laser capture microdissection and RT-qPCR to measure microRNA abundance in nephron segments, pinpointing microRNA changes principally to glomeruli and proximal tubules. Our data describe a unique microRNA signature for IRI in the rat kidney. Pulsatile IPC reduces kidney damage following IRI and diminishes this microRNA signal. We have also identified candidate microRNAs that may act as biomarkers of injury and therapeutic targets in this context.
Bio-based polyurethane nanocomposite thin coatings from two comparable POSS with eight same vertex groups for controlled release urea
Authors: Li Lixia , Wang Meng , Wu Xiandong , Yi Wenping , Xiao Qiang
Published: May 2021

Nanocomposite modification has attracted much attention in improving properties of bio-based polymer coating material for coated fertilizer. Herein two comparable polyhedral oligomeric silsesquioxanes (POSS), with eight poly(ethylene glycol) (PEG) and octaphenyl groups attached to the cage, respectively, were successfully incorporated into thin castor oil-based polyurethane coatings via in-situ polymerization on the urea surface. The nanostructure coatings are environmentally friendly, easy to prepare, and property-tunable. The results show that the vertex group of POSS had a pronounced influence on dispersion level and interaction between polyurethane and POSS that well-tuned the release pattern and period of coated urea, even at the coating rate as low as of 2 wt%. The liquid POSS with long and flexible PEG groups had better compatibility and dispersibility in polyurethane matrix than the solid POSS with rigid octaphenyl groups, as evidenced by SEM/EDS. The unique properties were resulted from the different extents of physical crosslinkings. This modification of bio-based polyurethane coating with POSS provided an alternative method of regulating and controlling the properties of coated fertilizer.
Effects of the depth of the acetabular component during simulated acetabulum reaming in total hip arthroplasty
Authors: Zuo Jianlin , Xu Meng , Zhao Xin , Shen Xianyue , Gao Zhongli , Xiao Jianlin
Published: May 2021

We aimed to evaluate whether there are differences in the rotation center, cup coverage, and biomechanical effects between conventional and anatomical technique. Computed tomography scans of 26 normal hips were used to simulate implantation of acetabular component. The hip rotation center and acetabular component coverage rate were calculated. Moreover, a finite element model of the hip joint was generated to simulate and evaluate the acetabular cup insertion. Micromotion and the peak stress distribution were used to quantify the biomechanical properties. The medial and superior shifts of the rotation center were 5.2 ± 1.8 mm and 1.6 ± 0.7 mm for the conventional reaming technique and 1.1 ± 1.5 mm and 0.8 ± 0.5 mm for anatomical technique, respectively. The acetabular component coverage rates for conventional reaming technique and anatomical technique were 86.8 ± 4% and 70.0 ± 7%, respectively. The micromotion of the cup with conventional reaming technique was greater than that with anatomical technique. The peak stress concentration was highest in the superior portion with conventional reaming technique, whereas with anatomical technique, there was no stress concentration. Paradoxically although the acetabular component coverage rate is larger with conventional reaming technique, anatomical technique provides less micromotion and stress concentration for initial cup stability. Thus, anatomical technique may be more suitable for acetabulum reaming during primary total hip arthroplasty.
Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
Authors: Pérez-Santamarina Estela , García-Ruiz Pedro , Martínez-Rubio Dolores , Ezquerra Mario , Pla-Navarro Irene , Puente Jorge , Martí María José , Palau Francesc , Hoenicka Janet
Published: May 2021

Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.
Use of single guided Cas9 nickase to facilitate precise and efficient genome editing in human iPSCs
Authors: Li Pan P. , Margolis Russell L.
Published: May 2021

Cas9 nucleases permit rapid and efficient generation of gene-edited cell lines. However, in typical protocols, mutations are intentionally introduced into the donor template to avoid the cleavage of donor template or re-cleavage of the successfully edited allele, compromising the fidelity of the isogenic lines generated. In addition, the double-stranded breaks (DSBs) used for editing can introduce undesirable “on-target” indels within the second allele of successfully modified cells via non-homologous end joining (NHEJ). To address these problems, we present an optimized protocol for precise genome editing in human iPSCs that employs (1) single guided Cas9 nickase to generate single-stranded breaks (SSBs), (2) transient overexpression of BCL-XL to enhance survival post electroporation, and (3) the PiggyBac transposon system for seamless removal of dual selection markers. We have used this method to modify the length of the CAG repeat contained in exon 7 of PPP2R2B. When longer than 43 triplets, this repeat causes the neurodegenerative disorder spinocerebellar ataxia type 12 (SCA12); our goal was to seamlessly introduce the SCA12 mutation into a human control iPSC line. With our protocol, ~ 15% of iPSC clones selected had the desired gene editing without “on target” indels or off-target changes, and without the deliberate introduction of mutations via the donor template. This method will allow for the precise and efficient editing of human iPSCs for disease modeling and other purposes.
The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
Authors: Román Marie , García Laura , Morales Myrna , Crespo María J.
Published: May 2021

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.
Application of the targeted sequencing approach reveals the single nucleotide polymorphism (SNP) repertoire in microRNA genes in the pig genome
Authors: Pawlina-Tyszko Klaudia , Semik-Gurgul Ewelina , Gurgul Artur , Oczkowicz Maria , Szmatoła Tomasz , Bugno-Poniewierska Monika
Published: May 2021

MicroRNAs (miRNAs) are recognized as gene expression regulators, indirectly orchestrating a plethora of biological processes. Single nucleotide polymorphism (SNP), one of the most common genetic variations in the genome, is established to affect miRNA functioning and influence complex traits and diseases. SNPs in miRNAs have also been associated with important production traits in livestock. Thus, the aim of our study was to reveal the SNP variability of miRNA genes in the genome of the pig, which is a significant farm animal and large-mammal human model. To this end, we applied the targeted sequencing approach, enabling deep sequencing of specified genomic regions. As a result, 73 SNPs localized in 50 distinct pre-miRNAs were identified. In silico analysis revealed that many of the identified SNPs influenced the structure and energy of the hairpin precursors. Moreover, SNPs localized in the seed regions were shown to alter targeted genes and, as a result, enrich different biological pathways. The obtained results corroborate a significant impact of SNPs on the miRNA processing and broaden the state of knowledge in the field of animal genomics. We also report the targeted sequencing approach to be a promising alternative for the whole genome sequencing in miRNA genes focused studies.
Diversification of the Balloon bushcrickets (Orthoptera, Hexacentrinae, Aerotegmina) in the East African mountains
Authors: Grzywacz Beata , Warchałowska-Śliwa Elżbieta , Kociński Maciej , Heller Klaus-Gerhard , Hemp Claudia
Published: May 2021

East African mountains constitute a network of isolated habitat islands among dry savannah and are thus ideal for studying species diversification processes. This study elucidated the phylogenetic and phylogeographic relationships of all bushcricket species comprising the genusAerotegmina. Our analysis indicated that large-scale climatic and topographic processes in Africa are likely to have driven speciation in this group, and revealed the cytogenetic traits of the species. Molecular phylogeny supported the monophyly ofAerotegminaand showed that the genus probably originated in the old Eastern Arc Mountains of Tanzania and Kenya. Two lineages were distinguished: small- and large-sized species with geographically distinct habitats. The underlying processes are thought to be eight dispersals, ten vicariance events, and one extinction event linked to repeated fragmentation of the African rainforest. Those processes, in conjunction with habitat change, probably also led to the spatial separation of the species into a northern clade with a diploid number of chromosomes 2n = 32 + X0 or 2n = 30 + neo-XY and a southern clade with a reduced number of chromosomes (2n = 28 + X0 or 24 + neo-X1X2Y). Karyotype analysis suggests thatAerotegminais currently in the process of speciation.
Role of hydrogen bond alternation and charge transfer states in photoactivation of the Orange Carotenoid Protein
Authors: Yaroshevich Igor A. , Maksimov Eugene G. , Sluchanko Nikolai N. , Zlenko Dmitry V. , Stepanov Alexey V. , Slutskaya Ekaterina A. , Slonimskiy Yury B. , Botnarevskii Viacheslav S. , Remeeva Alina , Gushchin Ivan , Kovalev Kirill , Gordeliy Valentin I. , Shelaev Ivan V. , Gostev Fedor E. , Khakhulin Dmitry , Poddubnyy Vladimir V. , Gostev Timofey S. , Cherepanov Dmitry A. , Polívka Tomáš , Kloz Miroslav , Friedrich Thomas , Paschenko Vladimir Z. , Nadtochenko Victor A. , Rubin Andrew B. , Kirpichnikov Mikhail P.
Published: May 2021

Here, we propose a possible photoactivation mechanism of a 35-kDa blue light-triggered photoreceptor, the Orange Carotenoid Protein (OCP), suggesting that the reaction involves the transient formation of a protonated ketocarotenoid (oxocarbenium cation) state. Taking advantage of engineering an OCP variant carrying the Y201W mutation, which shows superior spectroscopic and structural properties, it is shown that the presence of Trp201 augments the impact of one critical H-bond between the ketocarotenoid and the protein. This confers an unprecedented homogeneity of the dark-adapted OCP state and substantially increases the yield of the excited photoproduct S*, which is important for the productive photocycle to proceed. A 1.37 Å crystal structure of OCP Y201W combined with femtosecond time-resolved absorption spectroscopy, kinetic analysis, and deconvolution of the spectral intermediates, as well as extensive quantum chemical calculations incorporating the effect of the local electric field, highlighted the role of charge-transfer states during OCP photoconversion.
ARP-T1-associated Bazex–Dupré–Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies
Authors: Park Hyun-Sook , Papanastasi Eirini , Blanchard Gabriela , Chiticariu Elena , Bachmann Daniel , Plomann Markus , Morice-Picard Fanny , Vabres Pierre , Smahi Asma , Huber Marcel , Pich Christine , Hohl Daniel
Published: May 2021

Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics.
Identification of a peptide motif that potently inhibits two functionally distinct subunits of Shiga toxin
Authors: Watanabe-Takahashi Miho , Tamada Masakazu , Senda Miki , Hibino Masahiro , Shimizu Eiko , Okuta Akiko , Miyazawa Atsuo , Senda Toshiya , Nishikawa Kiyotaka
Published: May 2021

Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli, which causes fatal systemic complications. Here, we identified a tetravalent peptide that inhibited Stx by targeting its receptor-binding, B-subunit pentamer through a multivalent interaction. A monomeric peptide with the same motif, however, did not bind to the B-subunit pentamer. Instead, the monomer inhibited cytotoxicity with remarkable potency by binding to the catalytic A-subunit. An X-ray crystal structure analysis to 1.6 Å resolution revealed that the monomeric peptide fully occupied the catalytic cavity, interacting with Glu167 and Arg170, both of which are essential for catalytic activity. Thus, the peptide motif demonstrated potent inhibition of two functionally distinct subunits of Stx.
FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis
Authors: Shen Zhifa , Liu Bowen , Wu Biting , Zhou Hongyin , Wang Xiangyun , Cao Jinling , Jiang Min , Zhou Yingying , Guo Feixia , Xue Chang , Wu Zai-Sheng
Published: May 2021

Most hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells. The localization of mRNAs and their products to cell protrusions has been reported to play a crucial role in the metastasis. Our previous findings demonstrated that STAT3 mRNA accumulated in the protrusions of metastatic HCC cells. However, the underlying mechanism and functional significance of this localization of STAT3 mRNA has remained unexplored. Here we show that fragile X mental retardation protein (FMRP) modulates the localization and translation of STAT3 mRNA, accelerating HCC metastasis. The results of molecular analyses reveal that the 3′UTR of STAT3 mRNA is responsible for the localization of STAT3 mRNA to cell protrusions. FMRP is able to interact with the 3′UTR of STAT3 mRNA and facilitates its localization to protrusions. Importantly, FMRP could promote the IL-6-mediated translation of STAT3, and serine 114 of FMRP is identified as a potential phosphorylation site required for IL-6-mediated STAT3 translation. Furthermore, FMRP is highly expressed in HCC tissues and FMRP knockdown efficiently suppresses HCC metastasis in vitro and in vivo. Collectively, our findings provide further insights into the mechanism of HCC metastasis associated with the regulation of STAT3 mRNA localization and translation.
Bifidobacterium response to lactulose ingestion in the gut relies on a solute-binding protein-dependent ABC transporter
Authors: Yoshida Keisuke , Hirano Rika , Sakai Yohei , Choi Moonhak , Sakanaka Mikiyasu , Kurihara Shin , Iino Hisakazu , Xiao Jin-zhong , Katayama Takane , Odamaki Toshitaka
Published: May 2021

This study aims to understand the mechanistic basis underlying the response of Bifidobacterium to lactulose ingestion in guts of healthy Japanese subjects, with specific focus on a lactulose transporter. An in vitro assay using mutant strains of Bifidobacterium longum subsp. longum 105-A shows that a solute-binding protein with locus tag number BL105A_0502 (termed LT-SBP) is primarily involved in lactulose uptake. By quantifying faecal abundance of LT-SBP orthologues, which is defined by phylogenetic analysis, we find that subjects with 107 to 109 copies of the genes per gram of faeces before lactulose ingestion show a marked increase in Bifidobacterium after ingestion, suggesting the presence of thresholds between responders and non-responders to lactulose. These results help predict the prebiotics-responder and non-responder status and provide an insight into clinical interventions that test the efficacy of prebiotics.